IN THIS ISSUE - Drug Development & Delivery

July/August 2012 Vol 12 No 6 www.drug-dev.com 

The science & business of drug development in specialty pharma, biotechnology, and drug delivery 

Philip Graham, 

PhD 

Deuterium 

Modification as a New 

Branch of Medicinal 

Chemistry to Develop 

Novel, Highly 

Differentiated Drugs 

Cindy H. Dubin 

Transdermal, 

Topical & 

Subcutaneous: 

Non-Invasive 

Delivery to Expand 

Product Line 

Extensions 

Jean Sung, 

PhD 

A Next-Generation 

Inhaled Dry Powder 

Delivery Platform 

IN THIS 

ISSUE 

INTERVIEW WITH 

CAISSON BIOTECH’S 

CEO 

THOMAS HARLAN 

Regulatory 

Harmony 18 

Gill King, MBA 

Joel Finkle 

Medicated 

Chewing Gum 20 

Shivang Chaudhary, 

MSPharm 

3E 

Trilogy 24 

David F. Scelba 

Addressing 

Solubility 26 

Rod Ray, PhD, PE 

Microneedle 

Technology 30 

Mikolaj Milewski 

Amitava Mitra 

Injection 

Molding 36 

Andrew Loxley, PhD 

Designing 

Autoinjectors 41 

Jonathan Wilkins, PhD 

Iain Simpson, PhD

July/August 2012 Vol 12 No 6 

PUBLISHER/PRESIDENT 

Ralph Vitaro 

rvitaro@drug-dev.com 

EXECUTIVE EDITORIAL DIRECTOR 

Dan Marino, MSc 

dmarino@drug-dev.com 

CREATIVE DIRECTOR 

Shalamar Q. Eagel 

CONTROLLER 

Debbie Carrillo 

CONTRIBUTING EDITORS 

Cindy H. Dubin 

John A. Bermingham 

Josef Bossart, PhD 

Katheryn Symank 

TECHNICAL OPERATIONS 

Mark Newland 

EDITORIAL SUPPORT 

Nicholas D. Vitaro 

ADMINISTRATIVE SUPPORT 

Kathleen Kenny 

Corporate/Editorial Office 

219 Changebridge Road, Montville, NJ 07045 

Tel: (973)299-1200 

Fax: (973) 299-7937 

www.drug-dev.com 

International 

Ralph Vitaro 

219 Changebridge Road 

Montville, NJ 07045 

Tel: (973) 299-1200 

Fax: (973) 299-7937 

E-mail: rvitaro@drug-dev.com 

Mailing List Rental 

Candy Brecht 

Tel: (703) 706-0383 

Fax: (703) 549-6057 

E-mail: cbrecht@mgilists.com 

Advertising Sales Offices 

West Coast 

Warren De Graff 

818 5th Avenue, Suite 301 

San Rafael, CA 94901 

Tel: (415) 721-0644 

Fax: (415) 721-0665 

E-mail: wjdegraff@drug-dev.com 

All editorial submissions are handled with reasonable care, but the publishers assume no responsibility for the safety 

of artwork, photographs, or manuscripts. Every precaution is taken to ensure accuracy, but publishers cannot accept 

responsibility for the accuracy of information supplied herein or for any opinion expressed. Drug Development & 

Delivery (ISSN) 1537-2898 is published 9 times in 2012, January/February, March, April, May, June, July/August, 

September, October, and November/December by Drug Delivery Technology LLC, 219 Changebridge Road, Montville NJ 

07045. Subscription rates: $120.00 for 1 year in the United States, Canada, and Mexico. $188.00 for 1 year outside 

the United States, Canada, and Mexico. All subscriptions are payable in US funds, drawn on US banks. Send payment 

to: Drug Development & Delivery LLC subscription Department, 219 Changebridge Road, Montville NJ 07045. Single 

copies (prepaid) $20.00, US, Canada, and Mexico; $25.00 in all other countries. Add $5.00 per order for shipping 

and handling. Periodicals Postage Paid at Montville, NJ 07045-9998 and additional mailing offices. Postmaster: 

please send address changes to Drug Development & Delivery, 219 Changebridge Road, Montville NJ 07045. All rights 

reserved under the US International and Pan-American Copyright Conventions. All rights reserved. No part of this 

publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including by 

photocopy, recording, or information storage and retrieval system, without written permission from the publisher. 

Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is 

granted by Drug Development & Delivery for libraries and other users registered with the Copywrite Clearance, 222 

Rosewood Drive, Danvers, MA 01923; phone: (978) 750-8400, fax: (978) 750-4470. 

Proud member of 

East & Midwest 

Patricia Loyas 

977 Wall St. 

Diamond Point, NY 12824 

Tel: (518) 668-4144 

Fax: (518) 668-9794 

E-mail: ployas@drug-dev.com

Drug Development & Delivery July/August 2012 Vol 12 No 6 

6 

Addressing 

Solubility 

“With BCS Class II compounds comprising 

an increasing percentage of compounds in 

our clients' discovery portfolios, Bend 

Research is positioned to continue to 

provide the highest-quality support and 

innovation for our clients' pipelines. This 

proactive support is focused on two crucial 

areas: (1) support of the existing 

technology platforms and (2) development 

of next-generation technologies.” 

p.26 

24 3E Trilogy: Entertain, Educate & 

Engage….Become an Infotainer 

David F. Scelba continues his multiple part series on effective 

messaging and communications in the life science industry. 

26 Addressing Solubility Challenges: 

Using Effective Technology & Problem- 

Solving for Delivery Solutions 

Rod Ray, PhD, reviews his spray-dried dispersion (SDD) 

technology, which is recognized as a reliable solution to oral 

bioavailability challenges because of its proven performance, 

predictable long-term stability, and excellent manufacturability. 

30 Recent Developments in Microneedle 

Technology for Transdermal Drug 

Delivery & Vaccination 

Mikolaj Milewski and Amitava Mitra highlight some of the recent 

advances in the field of microneedle-mediated transdermal drug 

delivery and vaccination, including summaries of preclinical 

pharmacokinetic data and a brief overview of clinical studies, 

encompassing the time period from 2010 to present day. 

36 Injection Molding in the 

Pharmaceutical Industry 

Andrew Loxley, PhD, and Brett Braker say many of the processes 

used to manufacture products within the pharmaceutical 

industry are unique to the particular product; however, there are 

also processes that have been borrowed and adapted from other 

manufacturing industries and successfully employed in the 

development of pharmaceutical products. One such example is 

injection molding. 

41 Mathematical Modelling for Faster 

Autoinjector Design 

Jonathan Wilkins, PhD, and Iain Simpson, PhD, believe a fast 

and effective approach to a better injection device design is a 

novel combination of mathematical modeling on a desktop PC, 

supported with complementary experimental data. 

46 A Next-Generation Inhaled Dry 

Powder Delivery Platform 

Jean C. Sung, PhD, says that while delivery of drugs via first- 

generation inhaled drug systems provides great advantages over 

oral or intravenous delivery, these systems also have inherent 

limitations, creating a tremendous opportunity for next- 

generation inhaled delivery platforms.

8 

New 

Medicines 

“Concert Pharmaceuticals, a clinical-stage 

biopharmaceutical company, uses deuterium to 

create and develop highly differentiated new 

medicines. This is a significant departure from 

the traditional use of deuterium modification 

as an analytical probe for metabolic studies. 

The company uses its DCE PlatformTM (Deuterium Chemical Entity) to develop new 

drugs that are designed to have first-in-class 

or best-in-class efficacy and/or safety. 

Deuterium modification provides a novel 

opportunity to develop new drugs by building 

upon existing scientific or clinical experience, 

potentially significantly reducing time, risk, 

and expense.” 

Drug Development & Delivery July/August 2012 Vol 12 No 6 Developing 

p.67 

51 Transdermal, Topical & Subcutaneous: 

Non-Invasive Delivery to Expand 

Product Line Extensions 

Special Feature: Contributor Cindy H. Dubin asked delivery 

system providers and contract developers and manufacturers to 

describe their products and service offerings in their respective 

areas of expertise and how they are changing the overall 

landscape of the transdermal, topical, and subcutaneous markets. 

59 Caisson Biotech: Innovation in Drug 

Delivery Using a Naturally Occurring 

Sugar Molecule 

Drug Development Executive: Thomas Harlan, CEO of Caisson, 

discusses how his company is improving the quality and delivery 

of numerous medications, making life easier for patients, and 

offering new ways for companies to enhance their drug pipeline. 

67 Deuterium Modification as a New 

Branch of Medicinal Chemistry to 

Develop Novel, Highly Differentiated 

Drugs 

Philip Graham, PhD; Julie Liu, PhD; and David Turnquist, MBA; 

show that deuterium modification may be used broadly to 

improve upon previously known compounds or their analogs, in 

turn offering potential benefits in a wide range of therapeutic 

areas. 

71 Accera, Inc: Discovering 

Breakthroughs in Treating Central 

Nervous System Disorders 

Executive Summary: Holger Kunze, CEO of Accera, discusses the 

company's novel approach to treating AD by addressing cerebral 

hypometabolism. 

DEPARTMENTS 

Market News & Trends . . . . . . . . . . . . . . . . . . . . . 12 

Regulatory Review . . . . . . . . . . . . . . . . . . . . . . . . 18 

A Shrinking World: Realizing Regulatory Harmony 

Excipient Update . . . . . . . . . . . . . . . . . . . . . . . . . 20 

Directly Compressible “Medicated Chewing Gum 

(MCG)” for Staying Alert 

Technology & Services Showcase . . . . . . . . . . . . 62 

External Delivery . . . . . . . . . . . . . . . . . . . . . . . . . 74 

On Behalf of Private Equity


10 

Dan Marino, MSc 

Executive Director 

Drug Development 

& Delivery 

Shaukat Ali, PhD, 

MSc 

Technical Service Manager 

BASF Pharma Solutions 

Sarath Chandar, MBA 

Vice President, Global 

Marketing & Commercial 

Development 

SPI Pharma 

Ms. Debra Bingham 

Partner 

Valeo Partners 

Philip Green, PhD 

Senior Director, 

Drug Delivery Devices 

Merck Bioventures, 

Merck Research 

Laboratories 

James N. Czaban, JD 

Chairma, FDA Practice Group 

Wiley Rein LLP 

Josef Bossart, PhD 

Managing Director 

The Pharmanumbers Group 

Peter Hoffmann, PhD 

Biopharmaceutical 

Executive 

James D. Ingebrand, 

MBA 

VP & General Manager 

3M Drug Delivery 

Systems 

The 

EDITORIAL 

Advisory Board 

John A. 

Bermingham 

Co-President & COO 

Agratech, Inc. 

Derek G. Hennecke 

President & CEO 

Xcelience 

Clifford M. 

Davidson, Esq. 

Founding Partner 

Davidson, Davidson & 

Kappel, LLC 

Keith Horspool, PhD 

Vice President, 

Pharmaceutics 

Boehringer Ingelheim 

Uday B. Kompella, 

PhD 

Professor, Department of 

Pharmaceutical Sciences 

University of Colorado 

Denver 

Marc Iacobucci, 

MBA 

VP, Marketing & Project 

Management 

DPT Laboratories 

Cornell Stamoran 

VP, Strategy & Corporate 


Catalent Pharma 

Solutions 

Beth A-S. Brown, PhD, 

MS 

Senior Research Scientists II, 

Formulation & Process 


Gilead Sciences 

Der-Yang Lee, PhD 

Senior Research Fellow 

Global Technology, R&D, 

McNeil Consumer Healthcare, 

Johnson & Johnson 

Gary W. Cleary, PhD, 

PharmD, MBA 

President & CTO 

Corium International 

John Fraher 

President 

Aptalis Pharmaceutical 

Technologies 

Firouz Asgarzadeh, 

PhD 

Melt Extrusion Strategic 

Team Lead 

Evonik-Degussa 

Corporation 

James W. McGinity, 

PhD 

Professor of Pharmaceutics 

University of Texas 

at Austin 

Wei-Guo Dai, PhD 

Fellow, Drug Delivery & 

Device Development 

J&J Pharmaceutical R&D, 

LLC 

Matthew D. Burke, PhD 

Principal Scientist, 

Exploratory Pharmaceutics 

GlaxoSmithKline 

Robert W. Lee, PhD 

Vice President, 

Pharmaceutical 


Particle Sciences


12 

GSK Successfully Uses Capsugel’s Licaps 

Capsugel recently announced that its Licaps liquid-filled 

hard capsules have been successfully used by major 

healthcare company, GlaxoSmithKline (GSK), for the most 

established brand in the German urological market, GRANU 

FINK. 

After initially launching the product in a soft gelatin 

capsule form, GSK’s Consumer Healthcare Division decided to 

investigate other dosage form options to try and improve the 

product’s quality and reduce its production-to-market lead time. 

GRANU FINK’s active ingredients, pumpkin seeds extracts, 

and pumpkin oil, were challenging to encapsulate because of 

the large particle size and required a long maturing period 

when encapsulated in traditional softgels. After testing a switch 

to Capsugel’s Licaps technology, GSK found the product to be 

leak-free and have now reduced their product lead times by an 

amazing 12 weeks. 

"After comparing two different automated capsule sealing 

techniques, the Licaps capsules had intact seals during the 

complete period of stability testing, and we could not detect 

any leakage,” said Dr. Stephan Wurtz, Head of Production at 

GSK in Herrenberg. “Capsule integrity is a key parameter used 

to predict product shelf-life and especially helps with 

preventing too many product returns, and this is why we 

ultimately chose the Licaps liquid-filled hard capsules as our 

dosage form." 

Since Licaps capsules entered the market nearly 10 years 

ago, Capsugel has made multiple technological advances, 

including an enhanced mechanical seal with a seal zone six 

times greater than a banded capsule. And while they are able to 

effectively mask taste and odor, Licaps capsules also offer 

many branding options that may improve loyalty when 

compared with other dosage forms. According to Capsugel’s 

research, consumers perceive Licaps capsules to be highquality, 

modern, and natural looking in a dosage form that is 

memorable, easy to recognize, and easy to swallow. GSK also 

conducted their own consumer survey to test the visual and 

handling acceptance of the Licaps dosage form among regular 

users of GRANU FINK femina, and 73% of consumers were 

positive about the new Licaps liquid-filled hard capsule format. 

And Licaps liquid-filled hard capsules provide a solution 

for a variety of challenging compounds. It can improve 

bioavailability for poorly soluble compounds while providing 

effective formulation options for low-melting point compounds 

and safe formulation of low-dose/high potency actives. Licaps 

manufacturing also offers an established and robust process 

with the flexibility to allow for production in-house or by 

Capsugel. With a straightforward manufacturing transfer, 

including the installation of Liquid Encapsulation Microspray 

Sealing (LEMS) technology, Licaps capsules can even use the 

same line as powder-filled capsules and are sealed and dried in 

a matter of minutes, making manufacturing a cost-effective and 

environmentally friendly process. 

"The Licaps system has integrated well with our Bosch 

capsule filling equipment, and because of the expert technical 

assistance we had from Capsugel's installation and formulation 

teams, we put in place a number of new validated production 

processes with five fully trained operators in a very short 

time,” added Dr. Wurtz. “During one shift using the Licaps 

system, up to 350,000 Licaps capsules can be filled. We now 

have full in-house control of the manufacture of our drug and 

supplement lines, which gives us a number of benefits."


14 

Cook Pharmica Receives Milestone FDA Approval 

Cook Pharmica LLC recently announced it has received its 

first approval from the US FDA to manufacture 

commercial product. The product approval for commercial 

manufacturing came from the FDA’s Center for Biologics 

Evaluation and Research following a rigorous pre-approval 

inspection of Cook Pharmica in February. The inspection 

covered the company’s new vial filling line, lyophilization 

capabilities, and facility-wide quality systems. 

“This FDA decision marks a very important milestone for 

our company,” said Tedd Green, President of Cook Pharmica. 

“This first commercial manufacturing approval opens Cook 

Pharmica’s doors to the vibrant biopharmaceutical industry as it 

generates breakthroughs for patients in the United States and 

worldwide.” 

Company executives noted that the FDA’s approval of its 

vial filling line and lyophilization (freeze-drying) capabilities 

has already generated widespread industry interest in its full 

manufacturing and packaging capabilities, with inquiries coming 

from many leading biopharmaceutical companies. The rigorous 

preapproval inspection is a prerequisite for commercial 

Catalent & Bend Research Form Strategic Partnership 

Catalent Pharma Solutions, Inc. and Bend Research Inc. 

recently announced they have entered into an agreement to 

provide integrated solutions for pharmaceutical companies 

seeking to develop and manufacture specialized multiparticulate 

oral controlled-release products. 

Under the agreement, Bend Research and Catalent will 

provide an integrated approach to bring complex controlled- 

release products to market faster and more efficiently with 

optimal therapeutic and release profiles. 

The companies’ combined expertise in formulation 

development and Catalent's breadth of services in 

analytical/CMC, solid-state optimization, clinical and 

commercial supply will provide pharmaceutical companies with 

optimal dosage forms and a more efficient path to market. 

Catalent and Bend Research are developing joint operations and 

technology-transfer protocols to make the customer experience 

seamless and efficient while leveraging the strengths of both 

companies to develop better treatments for patients globally. 

“Our integrated approach is geared toward complex, 

multiparticulate controlled-release products, which traditionally 

have presented a high scale-up risk when they are transferred to 

manufacturing of clients’ drug product. 

“This approval demonstrates Cook Pharmica’s ability and 

commitment to manufacture high-quality drug products within 

the FDA’s stringent regulatory standards and practices. Everyone 

at Cook Pharmica is very pleased to have the opportunity and 

responsibility to ensure that we deliver a dependable commercial 

drug-product supply for our clients and ultimately to patients,” 

added Mr. Green. 

The parenteral manufacturing business unit of Cook 

Pharmica contains both vial and prefilled syringe manufacturing 

lines under barrier isolation, as well as secondary packaging to 

prepare products for distribution. Capable of filling 15 million 

vials and 70 million prefilled syringes annually, Cook 

Pharmica’s assets are available to fill the shortage of domestic 

drug product manufacturing in the United States and support 

federal efforts to eliminate dangerous drug shortages 

domestically. Based on other client projects at Cook Pharmica, 

the company expects to receive similar approvals to manufacture 

drug products for overseas markets as well. 

commercial manufacturing sites,” said Rod Ray, CEO of Bend 

Research. “This partnership with Catalent will provide an 

efficient pathway for these medicines from early development 

through commercialization. We believe that Catalent's breadth of 

services and demonstrated success in bringing controlled-release 

products to market, as well as supplying them globally, makes 

them an ideal complement to our development strengths.” 

“Catalent and Bend are aligning their scientific expertise 

and processes to ensure that developments are undertaken from 

Day One based on Quality by Design principles,” added Ian 

Muir, President of Catalent’s Modified Release Technologies 

business. “Bend’s added laboratory scale modeling expertise will 

enhance and increase the efficiencies that Catalent will provide 

to customers to bring difficult to formulate and manufacture 

controlled-release compounds to market faster, with optimal 

product profiles. This should enable optimal and seamless scale- 

up within Catalent’s Controlled Release network, and 

particularly at our Winchester, KY, facility, which is widely 

regarded as the leading commercial facility for multiparticulate 

products.”

Hovione Reports Significant Sales 

Growth 

Hovione recently announced that the consolidated sales 

for the fiscal year ended March 2012 amounted to 

$180 million, the sixth consecutive year of sales growth, 

representing a growth of 24% in relation to last year. 

“Another year of continued strong performance by the 

Hovione group. During the last 5 years, Hovione has 

doubled its sales and has made bold strategic steps to both 

strengthen its ability to serve innovators and to consolidate 

its leadership in off-patent contrast agents. Looking forward, 

and despite the difficult economic environment, we remain 

confident that 2012 will be another year of solid growth,” 

said Miguel Calado, Chief Financial Officer. 

In addition to the financial results, which reflect the 

quality of the Team’s performance, overall, 2011 represented 

a year of great achievements, namely Hovione stood behind 

three NDA approvals (these were all major NMEs) and in 

two cases, the approvals were full QbD filings in which 

Hovione was central to the design and data generation. 

All Hovione plants underwent several successful GMP 

inspections by one or more of the major Medicines’ 

Agencies - a reflection of the large flow of filings and the 

high standards of compliance. 

“Getting multiple NDA approvals every year is 

becoming a habit at Hovione, which reflects well both on 

our customers, on our team, and on the CMO model. Our 

patient investment in capacity, new technologies, and 

development methodologies is paying off.” said Guy Villax, 

Chief Executive Officer. 

Hovione is a global company with over 50 years’ 

experience in Active Pharmaceutical Ingredient and 

Intermediate Drug Product development and compliant 

manufacture. With four FDA-inspected sites in the US, 

China, Ireland, and Portugal, the company focuses on the 

most demanding customers, in the most regulated markets. 

Hovione offers integrated API, particle design, and 

formulation development and manufacturing. In the 

inhalation area, Hovione is the only independent company 

offering such a broad range of services. 


15


16 

AmDerma & Oculus Enter Multi-Country Agreement 

AmDerma Pharmaceuticals, LLC, a privately owned 

company (and parent company of Quinnova 

Pharmaceuticals, Inc.) and Oculus Innovative Sciences recently 

announced the execution of an agreement to develop and 

commercialize Oculus’ novel proprietary Microcyn Technology 

drug compounds for major dermatological conditions, including 

acne. The exclusive agreement includes licensing of the 

dermatology compounds in the US and India, with a first right 

of refusal for all member states of the European Union, Canada, 

Brazil, and Japan. Oculus retains all rights for the rest of the 

world. 

Under the terms of the agreement, Oculus received an 

undisclosed upfront payment, and will receive multiple clinically 

based payments upon achievement of several development and 

regulatory milestones for both acne and secondary indications, 

as well as future escalating double-digit royalties on net sales of 

products. The agreement also memorializes the intent for future 

joint development of additional dermatological products and 

indications. 

"This agreement reflects the AmDerma/Quinnova 

commitment to the future of dermatology. Microcyn compounds 

have the potential to bring about significant advancement in the 

treatment of skin diseases, which affect millions of patients, 

without adding to the growing problem of antibiotic resistance 

or steroid overuse," said Jeffrey Day, Quinnova President. "Our 

dermatology customers have been pleased with improved patient 

outcomes as a result of adopting the Microcyn-based 

compounds for treatment of atopic dermatitis and related skin 

diseases. We look to build upon this success by growing the 

family of Microcyn-based dermatology compounds for myriad 

skin afflictions." 

AmDerma will be responsible for the development costs for 

the acne formulation as well as other dermatological 

compounds. 

"Oculus is thrilled to expand the scope of our existing 

partnership with Quinnova and its parent company, AmDerma. 

Quinnova is doing an exceptional job with the commercial 

launch of the Atrapro product, and we are confident they are the 

right partner to commercialize this technology in acne and other 

dermatological indications," said Hoji Alimi, Founder and 

President of Oculus.

Ambrx & Merck to Design & Develop Biologic Drug Conjugates 

Ambrx recently announced the company has entered into a 

collaboration with Merck to design and develop rationally 

optimized biologic drug conjugates based on Ambrx's site- 

specific protein medicinal chemistry technology. 

"Ambrx's technology has the potential to provide the 

foundation for a new family of biologic drug conjugates that 

selectively deliver small molecules to their site of action," said 

Peter G. Schultz, PhD, a scientific founder and board member. 

"Merck's deep disease area expertise made it the partner of 

choice in expanding the application of this technology beyond 

oncology to other important disease areas." 

Under the terms of the agreement, Merck gains worldwide 

rights to develop and commercialize biotherapeutic drug 

conjugates directed toward a number of pre-specified targets. 

Ambrx will receive an upfront payment of $15 million and is 

eligible to receive milestone payments totaling up to $288 

million for successful discovery, development, and 

commercialization of candidates to all pre-specified targets. In 

addition, Ambrx will receive royalties on any net sales of 

products resulting from the collaboration. 

"Collaborations are an important part of our strategy to 

develop a portfolio of next-generation protein therapeutics that 

may offer significant benefits to patients," said Richard Murray, 

PhD, Senior Vice President and Head of Biologics and Vaccines 

Research at Merck. "This agreement will allow us to combine 

Ambrx's expertise in site-specific protein conjugation chemistry 

with Merck's expanding antibody capabilities and extensive 

small molecule resources." 

By combining the targeting properties of biologics with the 

potent therapeutic properties of small molecules, Merck and 

Ambrx plan to design and optimize new ways to specifically 

deliver pharmacologically active compounds to their site of 

action while minimizing the potential for systemic effects. 


17


18 

A Shrinking World: Realizing Regulatory Harmony 

By: Gill King, MBA, and Joel Finkle 

The life sciences industry faces a number of tough challenges in 

2012 - not the least of them the growing reach of increasingly 

onerous regulatory requirements. 

While new international market opportunities are emerging all 

the time, exploiting them remains challenging because of the differing 

ways each region and country handle regulatory submissions. Even 

when submissions follow the guidance of the International Conference 

on Harmonization (ICH) - which indeed has brought greater cohesion 

to the ways such activities are managed across the three major 

markets of the US, the European Union (EU), and Japan - there 

remain differences in interpretation involving submission formats, 

such as the electronic Common Technical Document (eCTD). To be 

able to take full advantage of all of the market opportunities open to 

them, companies must ensure their submissions can meet the 

requirements of the evolving formats, the developing standards, and 

the old and new regulations stipulated by the respective authorities. 

The following explores some of the major developments that 

have taken place throughout the past year in major markets and what 

those developments mean for the industry in the future. 

FDA SAFETY DRIVE PROMPTS MODERNIZATION 

Throughout the past 1 or 2 years, the US FDA has adopted an 

increasingly aggressive approach to ensuring patient safety, triggering 

a shake-up in quality control across all aspects of drug production and 

marketing. As part of its modernization drive, the FDA has been 

working collaboratively with standards-setting bodies - in particular, 

the Clinical Data Interchange Standards Consortium - to develop 

standards for the submission of study data. The efforts of such bodies 

have resulted in the development of numerous clinical standards, such 

as the Study Data Tabulation Model for representation of clinical trial 

tabulations, the Analysis Data Model for clinical trial analysis files, 

and the Standard for Exchange of Nonclinical Data for representation 

of nonclinical animal toxicology studies tabulations. 

Although adoption has been largely voluntary, the FDA, having 

developed standards in accordance with the industry’s requests, now 

expects companies to adopt the standards more consistently. That 

includes the way regulatory submissions get made. From 2015, all 

submissions will need to be filed in eCTD format. The Center for 

Drug Evaluation and Research (CDER) already receives 400 to 600 

electronic submissions per day; 70% of NDAs are eCTDs, and even 

INDAs are gathering momentum, with 52% of INDs now filed as 

eCTDs. 1 

MODULE 1, VERSION 2 

Each agency participating in the ICH eCTD standard has its own 

requirements for the Module 1, or Regional, section. The FDA has 

just released draft guidance for an updated version of its Module 1 

specifications. For drug sponsors, two aspects of the new Module 1 

guidance are probably most significant: the introduction of bundled 

submissions and the decision to bring marketing submissions into the 

eCTD fold. 

The right to bundle submissions offers huge time and costsavings 

for the industry by allowing information from more than one 

product or regulatory activity to be sent in a single package. In the 

meantime, the FDA department that handles marketing submissions 

has been designated an office in its own right - the Office of 

Prescription Drug Promotion (OPDP) - and there is now greater 

differentiation between promotional material for healthcare 

professionals and that for direct-to-consumer advertising. 2 

Once the updated Module 1 has been implemented, the OPDP 

will accept eCTDs through the electronic gateway, and new headings 

and a altered hierarchy mean companies will have to use only one 

kind of software to send material to the FDA. There remain some 

issues to address, and Module 1 is currently under review. Final 

guidance is expected to be issued at the end of 2012, with 

implementation starting no earlier than January 2013 as part of a 

phased transition. 3 

EU TURBULENCE MIXED ECTD UPTAKE 

The fragile euro isn’t the only source of turmoil in Europe. 

Regulatory submission management behavior is similarly inconsistent. 

The eCTD is now well established at the European Medicines Agency, 

which mandated the eCTD for the Centralized Procedure as of 

January 2010. 4 Yet the Centralized Procedure accounts for only 11% 

of EU submissions. Of the remaining 89%, 12.7% are under the 

Mutual Recognition Procedure, 23.8% are under the National 

Procedure, and 61.8% are under the Decentralized Procedure. 

The EU has also struggled to gain much buy-in for the so-called 

variation guideline, implemented in 2010. In the past, no matter what 

change was being made to a product license, companies had to get 

approval first. In an attempt to minimize the administrative burden, 

the European Medicines Agency has permitted companies to 

implement variations by simply submitting an annual report to the 

agency within 12 months. In practice, however, the processes that 

have been instituted at most companies in Europe don’t allow for an 

automatic trigger that advises when to send something to the agency.

Further guidance covers work-sharing 

procedures and grouped variations, which the 

FDA is just now catching up to via its draft 

Module 1 specification’s bundled applications, 

but the guidance needs updating to cater to 

eCTD submissions. The uptake has been 

slower than the health agencies might have 

hoped a situation now compounded by the 

EudraVigilance Medicinal Product Dictionary 

(EVMPD) mandate requiring that by July 2 of 

this year, marketing authorization holders 

submit comprehensive EVMPD data for every 

medicinal product authorized in the EU. 

JAPAN & CHINA COMMIT TO 

ECTD 

The eCTD is now well accepted by the 

Japanese regulatory authority, the 

Pharmaceuticals and Medical Devices Agency 

(PDMA), and to date, the agency has received 

106 official eCTDs. 5 

The PDMA updated its eCTD questionand-answer 

section in April 2011 and 

announced that companies in the industry 

could now e-mail questions to the agency.6 In 

addition, the PDMA released eCTD validator 

version 2.0 in February 2011, the first time 

the tool had been revised since its release 2 

years earlier. The new release streamlines 

processes and makes it more adaptable for 

companies. In July 2011, the PDMA released 

the fourth edition of the eCTD Creation 

Guide, which included not only updates by the 

Japanese authority but also industry best 

practices and experience. Companies are also 

better able to share information through the 

Japan eCTD Forum, which in October 2011, 

introduced an English home page. The forum 

is open to companies that have submitted 

eCTDs, and to date, all 37 companies that 

have submitted eCTDs to the authority have 

joined. 6 

Meanwhile, China’s State Food and Drug 

Administration (SFDA) has taken firm steps 

to adopt processes that are more in line with 

international submission standards and has 

been looking at ways of implementing the 

eCTD. 6 While most submissions are still 

required to be in paper format, the agency has 

taken several steps toward electronic adoption. 

For one thing, it provides an electronic 

application form, which includes summaries 

of each of the different parts of the 

submission. At the evaluation stage, the SFDA 

requests certain elements in electronic format, 

including quality specifications, packaging, 

labeling, the manufacturing process, and the 

clinical databases. At the marketing phase, 

companies are being asked to submit 

electronic copies of their adverse-drugreaction 

reports, their quality specifications, 

and their ongoing package inserts. 

The SFDA is even working to set up a 

safe e-submissions gateway, similar to the 

FDA’s Electronic Submissions Gateway. 

Before it does so, however, it needs to prepare 

its own internal systems to handle the 

electronic components. 

All of this will go a long way to appease 

multinational companies that have been eager 

for China to adopt ICH standards. At present, 

companies filing in China are finding they 

have to reformat entire submissions, and 

standardization would certainly serve to assist 

with the submission process. 

SUMMARY 

Efforts continue to create greater global 

standardization around the way submissions 

are formatted, though there’s clearly still a 

long way to go. The longer-term goal of 

harmonizing the submission process - at least 

among ICH member nations, through the 

Regulated Product Submission (RPS) - 

represents an ideal to aim for. The third draft 

of release 2 has been approved at HL7 as a 

Draft Standard for Test Usage and is now at 

ICH for testing. 

If all goes according to plan, the RPS is 

expected to achieve a normative standard by 

this time next year, with adoption by the FDA 

a year later. The RPS working group will also 

work to earn International Organization for 

Standardization certification - one of the 

conditions the rest of the ICH requires for its 

adoption. It is hoped the EU and Japan will 

then adopt the standard by 2015, allowing 

RPS to become the first true and 

internationally ratified standard. u 

REFERENCES 

1. Hussong G, CDER Presentation, Drug 

Information Association (DIA) Electronic 

Regulatory Submissions Meeting, 

November 2011. 

2. Kieste M, OPDP Presentation, DIA 

Electronic Regulatory Submissions 

Meeting. November 2011. 

3. Gray M, CDER Presentation, DIA 

Electronic Regulatory Submissions 

Meeting, November 2011. 

4. Wagner H-G, European Medicines Agency 

Presentation, DIA Electronic Regulatory 

Submissions Meeting, November 2011. 

5. eCTD in Japan, Atsushi Tomaru, Kyowa 

Hakko Kirin Co. Ltd., December 5, 2011. 

6. Section on China from December 7, 2011, 

discussion with Jeanie Kwon, Regulatory 

Operations Director, CSC Life Sciences. 

B I O G R A P H I E S 

Gillian King has 

worked in the 

pharmaceutical 

industry for over 12 

years, from 

establishing 

electronic document 

management systems 

for Europe, managing 

global submissions 

for NCEs, through to 

leading global 

functional teams. Her 

career has taken her into Pharmacovigilance, 

quality standards, and clinical operations, but her 

main focus is regulatory affairs and regulatory 

operations. Today, her role as Director, Head of 

Global Consulting within the Regulatory Solutions 

Group of CSC, allows her to immerse herself in 

challenging and complex business situations, and 

how organizational design, technology, and the 

regulatory environment work together to help 

achieve robust business operating models. Her 

achievements include setting up global regulatory 

operations groups and in establishing business 

processes and functional group design for global 

development and maintenance of products. She 

specializes in the “total view” and how cross 

functional departments must work together to 

achieve practical results. Ms. King earned her MBA 

from Warwick Business School, UK specializing in 

operations management and strategy. She can be 

reached at gking32@csc.com. 

Joel Finkle is 

Senior Strategist, 

Regulatory 

Informatics within 

CSC’s Regulatory 

Solutions Group 

(formerly ISI). He is 

the architect for two 

of their Document 

Creation solutions: 

ISIRender and 

ISIWriter. In his 

nearly 7 years, he has performed business process 

consulting, provided customizations to our 

solutions, and developed several software business 

partnerships. In his current role, he is working to 

find novel ways to solve regulatory software and 

service processes for customers, as well as 

providing the focal point for industry standards and 

regulatory guidance. Mr. Finkle comes from a 

background in the pharmaceutical industry, with 26 

years experience in software development and 

support of electronic submissions, publishing, and 

document templates, from custom CANDAs through 

eCTDs. He is currently a member of the HL7 

Regulated Product Submissions (RPS) standard 

development team, the DIA Electronic Regulatory 

Submission SIAC Core Team, the DIA Cross-SIAC 

EDM Reference Model development team, and the 

OASIS DITA Pharmaceutical Development Team. He 

can be reached at jfinkle@csc.com. 


19


20 

Directly Compressible “Medicated Chewing Gum 

(MCG)” for Staying Alert 

By: Shivang Chaudhary, MSPharm; Aliasgar Shahiwala, PhD; and Manju Misra, PhD, MPharm 

Medicated chewing gums are 

defined by the European 

Pharmacopoeia and the 

guidelines for pharmaceutical dosage forms 

as “solid single dose preparations with a 

base consisting mainly of gum that are 

intended to be chewed but not swallowed, 

providing a slow steady release of the 

medicine contained.” 1,2 They can be used for 

local treatment of mouth disease or 

systemic delivery by direct intraoral 

absorption through the buccal mucosa. 3 

Medicated chewing gums offer numerous 

advantages over other drug delivery 

systems, among which some important 

advantages are highlighted in this 

discussion. 

There is an increasing need to 

reformulate existing drugs into Novel Drug 

Delivery Systems (NDDS) to extend or 

protect product patents thereby delaying, 

reducing, or avoiding generic erosion at 

patent expiry. By formulating the drugs in 

MCG composition, revitalization of old 

products and reformulation of new patented 

products is possible to distinguish from 

future generics competition in the market. 

Medicated Chewing Gum (MCG) is a 

solid single-dose preparation comprising 

gum base and other ingredients and 

containing active ingredient(s) that are 

released by chewing and intended for quick 

onset of action by direct intraoral 

absorption into systemic circulation. 4 

Traditionally, MCG has remained as a 

niche category due to its complex 

formulation and manufacturing that uses 

hot mixing and extrusion procedures 

involving specific technology and 

equipment that most pharmaceutical 

companies are not familiar with. Moreover, 

the use of heat and liquids in these 

processes prevents many APIs from being 

considered due to their sensitivity to high 

temperature levels and moisture. 

However, in the recent past, a new 

door has opened with the launch of 

innovative directly compressible powder 

excipients for production of medicated or 

functional chewing gums. These are 

designed specifically to bring gum 

technology closer to pharmaceutical 

companies by adapting to traditional oral 

solid formulation and production 

requirements in the pharma industry. 

They are made as an “all in one” 

combination of different ingredients that 

promote long chewing consistency because 

they contain the essential gum base, and at 

the same time, they have great flowability 

and compressibility properties due to their 

polyol and glidant content in order to be 

easily compressed and adapt to 

pharmaceutical production standards. 

The combination of these ready-made 

gum excipients allows multiple possibilities 

of formulation with an active ingredient 

and different flavors of choice, all in a dry 

room temperature process. 

In the present study, MCG was 

formulated using Health in Gum ® directly 

compressible powder (gum powder) with 

100 mg of caffeine. Pharmacopoeia quality 

control parameters were measured along 

with a human volunteer study to measure 

the API release rate from the chewing gum 

matrix. 

Caffeine is a highly soluble and highly 

permeable central nervous system (CNS) 

stimulant used in management of fatigue 

and increasing alertness, and from studies, 

it has been revealed that chewing action 

itself enhances 25% blood flow to the brain 

resulting in improvement in alertness. 2,3 

Thus, caffeine chewing gum can address 

F I G U R E 1

the issues of staying alert in two ways: one 

from drug (caffeine) and another from a drug 

delivery system (chewing gum). Therefore, 

caffeine chewing gum can be a synergistic 

delivery option for staying alert, especially for 

professions in which staying alert for long 

periods of time is necessary and vital. 

FORMULATION DEVELOPMENT 

The starting raw material of the formulation is 

the gum powder, which will account for at 

least 85% of the total weight of the tablet in 

order to have chewing gum consistency over 

time. Once the API and flavor combination 

was figured out in the correct proportions, the 

mixing process started as follows: 

Mixing Procedure 

• Mixing of liquid flavor on the powder gum 

preparation for 5 minutes 

• Screening of the mixed preparation through 

No. 22 sieve 

• Mixing of API, antisticking agent, flavoring 

ingredients, lubricant, and glidant 

• Sieving and blending (10 minutes) 

Finally, the formulation was compressed. In 

process quality control (IP-QC), parameters 

for optimized batch are shown in Table 1, 

which indicates it had very good flow 

property and compressibility. 

CFN-MCG QUALITY EVALUATION 

A. OFFICIAL (BP/EP) 

PRODUCT QUALITY 

ASSESSMENT TESTS 

An assay for content uniformity and 

friability test was carried out as per European 

Parameters 

pharmacopoeia. The final MCG formulation 

passed the test for uniformity of mass; none 

deviated from ± 5% of average mass of MCG. 

All 10 MCGs, which were sampled randomly, 

have passed the test for uniformity of content 

because contents of CFN in all 10 MCGs have 

fallen within compliance limit of 85% to 

115%, and average content of CFN was found 

to be 99.21% ± 0.53%. In friability testing, 

after 100 rotations, total weight loss of 10 

MCG was found to be 0.14%, which was less 

than the compliance limit of 1.0%. Thus the 

final MCG formulations passed in friability 

test as well. 

CFN-MCG performance evaluation for 

determining the percent of drug release was 

obtained by a “Chew Out” study of six 

volunteers in which each person chewed one 

sample of the caffeine chewing gum for 

different time periods (5, 10, 15, and 20 

mins). Next, residual drug had been cut into 

small pieces, frozen, and then ground till 

obtaining fine powder, and then analyzed to 

determine residual drug content by UV visible 

spectrophotometer at 273 nm. 

So, actual drug content minus residual 

drug content equals released drug content 

from the MCG. 

The drug contained within the MCG is 

T A B L E 1 

Result With Indication 

Angle of repose of gum powder 29.11° - Very good as per EP 

Carr’s compressibility index of gum 

powder 

8.00 - Very good as per EP 

Compatibility of caffeine with gum In DSC spectrum, separate peaks at 92°C (xylitol), 95°C 

powder by DSC 

(sorbitol), and 236°C (caffeine) - No Incompatibility 

Results of properties of the powder gum. 

T A B L E 2 

released in the saliva for the duration of the 

chewing process, and then it would be either 

absorbed through the oral mucosa or if 

swallowed, would be absorbed through the 

gastrointestinal tract. Pharmacokinetics can be 

determined from withdrawn blood samples at 

specific time intervals. 

SELECTION & OPTIMIZATION 

OF FACTORS AFFECTING % 

DRUG RELEASE FROM MCG 

BY 3 2 FULL FACTORIAL 

EXPERIMENTAL DESIGN 

Independent significant factors, chewing 

time (A) and amount of gum powder (B), 

affecting dependent factor (% CFN release 

from MCG) were first extracted out by means 

of ANOVA, and then extracted factors were 

optimized by 32 full factorial experimental 

design. Here, full factorial 32 designs were 

used for the optimization procedure because it 

is suitable for investigating the quadratic 

response surfaces and for constructing a 

second-order polynomial model, thus enabling 

optimization of the chewing time and amount 

of gum base to achieve sufficient drug release 

from MCG. Mathematical modeling, 

No. Official Tests Observations Compliance Criteria Result 

01 Uniformity of Mass None deviated from ± 5% NMT 2 deviate from ± 5% Pass 

02 Uniformity of Content 

All 10 MCG contain CFN within 

limits 

85% < x < 115% Pass 

03 Friability Testing 

Total weight loss = 0.14% of 10 

MCG 

Weight loss < 1.00% Pass 

Results of official product quality assessment tests. 


21


22 

evaluation of the ability to fit to the model, 

and response surface methodology (RSM) 

were performed by employing Design-Expert ® 

software (Version 7.1.2, Stat-Ease Inc., 

Minneapolis, MN). RSM is a collection of 

mathematical and statistical techniques useful 

for the modeling and analysis of problems in 

which a response of interest is influenced by 

several variables and the objective is to 

optimize this response. The most extensive 

applications of RSM are in the industrial 

world, particularly in situations where several 

input variables potentially influence some 

performance measure or quality characteristic 

of the product or process. This performance 

measure or quality characteristic is called the 

response. 

A. 

B. 

Factors 

(Independent Variables) 

Chewing time (mins.) 

Amount of gum powder 

(%) 

Table 3 summarizes the independent and 

dependent variables along with their coded 

and actual levels. A total of four experimental 

testing runs were conducted. 

It was illustrated from the surface 

response graph that as chewing time (A) 

increases, percent of drug release increases as 

well, but an increasing amount of gum 

powder (B) has very little drop-off effect on 

T A B L E 3 

Results of official product quality assessment tests. 

Levels Used 

-1 0 +1 

5 

70 

10 

75 

T A B L E 4 

Experimental 

Variable Factors in Coded tTerms 

(Actual Terms) 

Test Run Chewing Time Amt. of Gum 

(mins.) 

Powder (%) 

1 -1(05) -1(70) 

2 0(10) -1(70) 

3 +1(15) -1(70) 

4 - 1(05) 0(75) 

5 0(10) 0(75) 

6 +1(15) 0(75) 

7 -1(05) +1(80) 

8 0(10) +1(80) 

9 +1(15) +1(80) 

Experimental testing runs with values of variable factors. 

15 

80 

Response 

(Dependent Variables) 

% Drug Release 

percent of caffeine release. Specifically: % 

Drug Release = + 88.33 + 5.67 A - 1.50 B + 

0.25 AB - 2.00 A²- 0.50 B². 

The quadratic models generated by 

regression analysis were used to construct a 

two-dimensional contour plot and threedimensional 

response surface plot in which 

response parameter DR was represented by a 

curvature surface as a function of A and B. 

Figure 1 shows the effect of chewing time and 

amount of gum powder in contour plot as well 

as response surface plot. 

A numerical optimization technique 

using the desirability approach was employed 

to develop a new formulation with the desired 

responses. In this study, optimization was 

performed with constraints for DR (90% < 

DR < 95%) set as goals to locate the optimum 

settings of the independent variables in the 

new formulation. The optimal parameters to 

achieve predicted CFN release of 92% (90% 

to 95%) as calculated from the predicted 

equation of drug release (A: chewing time = 

15 minutes, and B: amount of gum powder = 

75%). 

CONCLUSION 

Optimized formulation of directly 

compressed CFN-MCG has achieved the 

following: 

• Has passed all official MCG quality 

tests, including uniformity of mass, 

assay for uniformity of content, and 

friability testing as per compliance 

criteria mentioned in the official 

monograph of MCG in BP. 

• Released an average 92% of CFN 

(n=6) within 15 minutes of chewing, 

which is half of the normal average 

chewing time, in an in vivo chew out 

study. 

• Interindividual variability in percent 

CFN-release was observed in only up 

to 1 to 3 minutes, afterward, much less 

interindividual variability was 

observed in percent CFN release. 

Thus, the present study demonstrated 

that CFN could be successfully delivered by 

MCG into systemic circulation via direct 

intraoral buccal absorption. 

Concerning statistical analysis, it was 

shown that a 32 full factorial experimental 

design (FFED) and optimization technique 

can be successfully used in the development 

of an optimized formulation of MCG and for 

deciding appropriate chewing time for 

sufficient drug release. The optimized 

formulation exhibited drug release profiles 

that were close to the predicted responses, 

which was confirmed by high significant r2 = 

0.988 (> 0.9) value. 

Based on the overall results, it was 

concluded that the developed formulation of 

directly compressible taste-masked MCG of 

caffeine presents a better alternative to any 

other dosage form, including tea or coffee, 

because it is a synergistic delivery option for

staying alert. Moreover, CFN-MCG can be 

taken anywhere and anytime without 

preventing the consumer from living an active 

life, which promotes higher acceptance and 

compliance. 

Moreover today, it is known that chewing 

gum has other benefits: it promotes oral 

health, it is a mild stress relief, and it reduces 

the appetite sensation, all of which are added 

positive characteristics that increase the value 

of a caffeine drug delivery system in the form 

of chewing gum.This eventually can lead to 

the development of a new attractive market 

directed to energy and sports products, which 

is already flourishing in occidental countries. 

Other potential applications for MCG 

include areas like allergy, cough and cold, 

digestive, and oral care, added to the 

consolidated available nicotine and motion 

sickness gums. u 

REFERENCES 

1. European Pharmacopoeia, 2.9.5., 2.9.6, 

2.9.7, 2.9.25, 2.9.36, 6th edition. 

2. Wilson and Gisvold's Textbook of Organic 

Medicinal and Pharmaceutical Chemistry. 

11th ed. New York, NY: Lippincott 

Williams & Wilkins Publishing; 2004:511- 

512. 

3. Adopted from 

www.chewinggumfacts.com/chewing-gumbenefits/health-benefits-of-gum-chewing. 

4. Jacobsen, Christrup-LL. Medicated 

chewing Ggum: Ppros and cons. Am J 

Drug Del. 2004;2(4):75-88. 


Shivang Chaudhary is a Formulation Scientist with a 

BPharm from Nirma University of Science & Technology, 

India, and an MSPharm in Pharmaceutics from the National 

Institute of Pharmaceutical Education & Research (NIPER), 

Ahmedabad. During his Masters he felt a necessity of 

reformulating existing drugs into Novel Drug Delivery 

Systems (NDDS) to extend or protect product patents 

thereby delaying, reducing, or avoiding generic erosion at 

patent expiry. Apart from this chewing gum containing 

Caffeine (Alllert®) for staying alert, he has also developed 

medicated chewing gum containing different drugs for various other diseases, such as 

MCG for Erectile Dysfunction (EreX®) in vanilla, chocolate, strawberry, wild cherry, 

pineapple, and butterscotch flavors; MCG for motion sickness (Gaglet®) in cardamom, 

orange, lemon(lime), and ginger flavors; MCG for Vit-B12 deficiency (Smirk®) in banana 

flavor; and MCG for acidity (Relaaax®) in peppermint and spearmint flavors. He strongly 

believed that by formulating the drugs in MCG composition, revitalization of old 

products and reformulation of new patented products is possible to distinguish from 

future generics competition in the global market. 

Dr. Aliasgar Shahiwala is currently working as an 

Associate Professor in Dubai Pharmacy College. Before 

joining Dubai Pharmacy College, he was associated with the 

National Institute of Pharmaceutical Education and 

Research-Ahmedabad, India. Dr. Shahiwala has earned 

Masters and Doctorate degrees in Pharmaceutics and 

Pharmaceutical Technology from The Maharaja Sayajirao 

University of Baroda, India, and has completed 1-year of 

post-doctoral research experience at Northeastern University, 

USA. He has more than 3 years of rich research experience 

in the formulation and development division of large-scale manufacturers of 

pharmaceuticals in India and more than 7 years of teaching experience at both the 

graduate and post-graduate level. His research credentials have established him a 

reviewer, a member of editorial board, a speaker, and an invited author for various 

pharmaceutical scientific journals and conferences. Dr. Shahiwala’s key strength is 

diversity of work experience in different settings. 

Dr. Manju Misra is currently serving as Assistant Professor 

at NIPER Ahmedabad. She has prior experience working as 

part of an ANDA formulation development team at Macleods 

Pharmaceuticals, Mumbai, and Cadila Pharmaceuticals, 

Ahmedabad. She earned her PhD from BIT Mesra, Ranchi, 

India, and her MPharm from Nagpur University, India. 


23


24 

MARKETING MATTERS 

3E Trilogy: Entertain, Educate & 

Engage…..Become an Infotainer 

A multiple part series on effective messaging and communications in the life 

science industry. 

By: David F. Scelba, Partner, LifeSciencePR

In my previous column (May 2012, 

page 24-25), I provided a general 

overview of my four trilogies and 

four simple steps to implementing a 

social media strategy. In this column, 

I’ll explain in greater detail my 3E 

Trilogy …Entertain, Educate & 

Engage. 

Now, it doesn’t really matter if 

you’re in the Life Science industry or 

frankly any other marketplace. The 

fact is that effective communications 

means commanding and keeping your 

audience’s attention, and the most 

effective way to keep their attention is 

to entertain them. 

One of the best teachers I had in 

high school was my history teacher 

Mr. De Nooyer. He was someone who 

clearly understood the importance of 

entertaining to educate, and he 

engaged every student, even those with 

challenging attention spans. As an 

example, he would dress up in colonial 

garb when he was discussing the 

Revolutionary War. He even wore a 

German uniform and spoke with a 

German accent to dramatize the 

unspeakable evils of the concentration 

camps of World War II. At the time, 

we all thought he was nuts, but the 

truth is, he was a master 

communicator. His classroom antics 

and theater helped the lessons “come 

alive” in an incredibly entertaining and 

memorable way. It’s been more than 40 

years since I sat in his class, but I can 

still remember his lessons like it was 

yesterday. Mr. De Nooyer was a 

teacher’s teacher and an incredible 

salesman. 

With today’s technologies and 

multiple social media outlets, Mr. De 

Nooyer’s entertaining lessons could 

have been delivered and distributed to 

an infinite number of virtual 

classrooms and inquisitive students 

throughout the world. 

But while YouTube, Facebook, 

Twitter, LinkedIn, Pinterest, and all the 

other social media outlets deliver 

content to the right targeted audiences, 

they won’t gain an audience if the 

content isn’t entertaining. 

The key to implementing a 

successful social media strategy is the 

development of interesting content 

and, of course, the creative execution. 

You’ve all heard the saying, “Content 

is King,” and it’s absolutely true, but 

only if it’s presented in an entertaining 

manner. 

By now everyone knows video is 

the most efficient and effective 

communications tactic used 

throughout all websites, blogs, social 

media networks, and mobile apps. Just 

as Mr. De Nooyer was never 

embarrassed about wearing uniforms 

or acting in front of the live class, you 

shouldn’t be self conscious or feel silly 

reading from a teleprompter in front of 

a video camera. 

So let your creative juices flow 

and become an “Infotainer” with the 

ultimate goal of entertaining your 

audience. If you develop good content 

and creatively present it, you’ll educate 

your audience and engage them in 

ongoing communications. Engagement 

acts as one measurement matrix of 

your content and creativity, and is an 

indicator of whether you’re doing a 

good job communicating. 

Entertain, Educate & Engage … 

my simple 3E Trilogy to better, more 

effectively, and efficiently leverage 

social media communications to 

achieve your company’s strategic 

marketing and communications 

initiatives! u 

B I O G R A P H Y 

David F. Scelba is the Founder and 

Chairman of SGW Integrated Marketing & 

Communications and is a Partner at 

LifeSciencePR. He is responsible for the 

development of the company’s new 

interactive products and services and plays a 

key role as senior strategist for developing 

clients’ integrated marketing 

communications programs. He is also 

involved in researching and investigating 

acquisition opportunities and for initiating 

negotiations on behalf of the company. As a 

consultant to the broadcast, computer, and 

telephone industries Mr. Scelba experienced 

the technology convergence first hand. This 

unique background provides him the ability 

to develop innovative products and services 

that generate the most cost-effective and 

efficient marketing strategies available 

today. His diversified B2B, consumer, and 

retail experience encompasses industries 

such as: automotive; biochemical; 

broadcast; education (K-12colleges/universities); 

healthcare; hospitals; 

life science; microwave; pharmaceutical 

(research/drug delivery); political; 

professional video/audio; medical; 

telecommunications; and more. He is a 

keynote motivational speaker whose 

audiences include marketing professionals, 

college professors, MBA graduate students, 

and undergraduates seeking careers in the 

marketing- and communications-related 

industries. He also mentors business and 

government leaders on the use of 

technologically innovative tools for better 

communication with their targeted 

audiences. Mr. Scelba earned his BA and MA 

in education, a CFP Certification, with series 

6 qualifications, Health/Life and Real Estate 

Licenses, which contribute to his common 

sense marketing philosophy. 


25


26 

BIOAVAILABILITY 

E N H A N C E M E N T 

Addressing Solubility Challenges: Using 

Effective Technology & Problem-Solving 

for Delivery Solutions 

By: Rod Ray, PhD, PE 

SCIENCE & TECHNOLOGY 

TO SOLVE 

BIOAVAILABILITY 

CHALLENGES 

Delivery of compounds with poor 

aqueous solubility is a common 

problem as more than 50% of new 

chemical entities fit into Class II of 

the Biopharmaceutical Classification 

System (BCS). BCS Class II 

compounds are poorly soluble but 

highly permeable, meaning that most 

cannot be absorbed during normal 

gastrointestinal transit times without 

an enabling formulation. 

While there are many types of 

enabling formulations that improve the 

solubility of low-solubility 

compounds, they are generally based 

INTRODUCTION 

Oral bioavailability represents a significant challenge to the pharmaceutical industry as more than half of the 

compounds in early development are considered poorly soluble. Bend Research, a problem-solving drug formulation 

development and manufacturing company, is well known for its spray-dried dispersion (SDD) technology, which is recognized 

as a reliable solution to this challenge because of its proven performance, predictable long-term stability, and excellent 

manufacturability. 

This review is a follow-up to an interview published in the May 2012 issue of Drug Development & Delivery in which the 

company’s background and problem-solving approach to drug delivery challenges faced by the pharmaceutical industry were 

discussed. 

on three approaches: (1) use of highenergy 

crystalline forms, such as salt 

forms, co-crystals, and crystals with 

reduced particle size; (2) dissolution 

of the drug in a lipid vehicle or lipid, 

solvent, and surfactant vehicle (to 

create a self-emulsifying dosage 

form); or (3) manufacture of an 

F I G U R E 1 

amorphous dispersion. Amorphous 

dispersions are generally 

manufactured by spray-drying or a 

hot-melt process. Each of these 

approaches is viable, depending on the 

compound’s physical and chemical 

properties, and all have been used for 

commercial pharmaceutical products.

CHOOSING THE APPROPRIATE 

TECHNOLOGY 

Bend Research takes an “agnostic” 

approach to choosing the appropriate 

solubilization technology, guided by a 

number of factors, including the 

compound’s physical-chemical properties, 

the projected dose, the desired release 

profile, and the results from numerous 

formulation and process models that we 

have developed throughout the past 

15 years. 

The goal in choosing the optimum 

solubilization technology is aimed at 

solving the right problem for that specific 

compound. Bend Research is capitalized 

for formulation development and cGMP 

manufacturing for spray-drying, hot-melt 

extrusion, and particle-size reduction to 

support our agnostic approach. 

Additionally, we can support the 

formulation of self-emulsifying and lipid 

formulations relying on a partner to 

complete the cGMP manufacturing. 

While we consider all possible 

technologies as we develop formulation 

approaches for poorly soluble compounds, 

our experience in the formulation of more 

than 500 low-solubility compounds is that 

spray-drying amorphous dispersions is the 

most widely applicable approach. This 

process involves dissolving the compound 

and a concentration-sustaining polymer in 

a volatile organic solvent that is rapidly 

removed in the spray dryer. This process 

allows for rapid drying of the formulation 

and isolation of the amorphous dispersion. 

It is widely applicable in that it avoids 

either melting the compound in a hot-melt 

process or relying on the solubility of the 

compound in a lipid vehicle. 

An additional benefit is that the 

spray-drying process has been scaled 

down to small scales compatible with 

early preclinical quantities of compound 

and scaled up to the multi-ton scales 

necessary for commercial manufacture. 

SPRAY-DRIED DISPERSIONS: 

KEY FACTORS & PROCESS 

OVERVIEW 

There are three key components to 

obtaining a high-performing amorphous 

dispersion. These are the spray-drying 

process conditions, the identification of 

the compound’s physical-chemical 

properties, and finally, the choice of 

excipients that are used in the amorphous 

dispersion. 

The spray-drying process is 

conceptually quite simple. Initially, the 

compound and a dispersion polymer are 

dissolved in a volatile organic solvent 

(e.g., acetone or methanol). The solution is 

then introduced into the drying chamber 

of a spray dryer along with heated 

F I G U R E 2 

nitrogen. The heated gas evaporates the 

solvent, leaving a dried powder, which is 

collected in a cyclone or baghouse. 

Of course, the process isn’t quite that 

simple. If the drying capacity of the 

nitrogen is insufficient, product will be 

deposited on the walls of the spray dryer, 

resulting in “spray-painting” and reduction 

of product yield. If the drying capacity of 

the nitrogen is overdesigned, energy costs 

are increased, and the risk of degrading a 

thermally labile compound is increased. 

However, by using best practices, 

spray-drying conditions can be identified 

that allow the product particles to be 

maintained at low temperatures (due to 

evaporative cooling as the volatile solvent 

evaporates), while producing high product 

yields (avoiding spray-painting of the 

walls of the dryer). These best practices 

for spray-drying process development 

were highlighted in a 2009 publication in 

the Journal of Pharmaceutical Innovation. 


27

COMPOUND PROPERTIES: 

AN IMPORTANT PART OF 

THE EQUATION 

Compounds with a wide variety of 

physical-chemical properties can be 

formulated as amorphous dispersions. 

During our decade-and-a-half formulating 

amorphous dispersions, we have found 

fewer than 10 compounds that could not 

be formulated as amorphous dispersions. 

These fall into two categories: (1) highly 

reactive compounds that chemically 

degrade in the amorphous state and 

(2) compounds with very high melting 

points that have poor physical stability or 

poor solubility in suitable spray solvents. 

However, this small group of compounds 

appears to be the exception rather than the 

rule. 

The vast majority of compounds we 

have worked on (out of more than 500 

tested) are amenable to formulation as 

amorphous dispersions, although their 

physical-chemical properties span meltingpoint 

ranges from 0°C to more than 350°C 

and log P values from less than 0 to more 

than 10. However, formulation 

compromises must be made for 

compounds at the extremes of physicalchemical 

property ranges to ensure 

performance is maintained. Generally, 

these compromises involve decreasing the 

amorphous dispersion drug loading or 

“swamping out” the poor drug properties 

by diluting the drug with the dispersion 

polymer. Of course, diluting the drug in 

polymer makes obtaining higher drug 

doses increasingly difficult. This is 

especially challenging in therapeutic areas 

such as anti-infectives, antivirals, and 

28 


oncology, in which high doses are 

typically needed. To address these classes 

of compounds, we have developed 

alternative technologies. 

These alternatives include a 

nanoadsorbate technology, in which a 

dispersion is coated on a high surface area 

support to increase the dissolution rate. 

This technology has been used in multiple 

clinical trials and notably has been used in 

the clinic to give dose-linear absorption of 

a log P 10 compound with a solubility of 

less than 10 ng/mL. To address the other 

extreme–compounds with very high 

melting points and a strong tendency to 

crystallize in both the solid state and 

solution–we have developed a crystallized 

dispersion technology in which small, 

tens-of-nanometer-sized crystals are 

intentionally formed in the dispersion. 

This approach maintains a high-energy 

form of the compound and prevents 

further crystallization of the compound to 

a lower-energy species. This technology 

has also been used to advance a number of 

compounds to clinical evaluation. 

THE IMPORTANCE OF 

EXCIPIENTS 

Excipient choice is critical and 

depends on the specific solubilization 

problem being solved. Recently, BCS 

Class II compounds have been 

subcategorized into DCS IIA and DCS IIB 

classes by Professor Dressman and coworkers 

from GlaxoSmithKline. DCS 

Class IIA compounds have inadequate 

dissolution rates, whereas DCS Class IIB 

compounds are truly solubility limited, 

making bioavailability difficult to achieve 

without concentration enhancing 

polymers. An added complication is that 

some compounds formulated as 

amorphous dispersions dissolve into 

solution and stay at that amorphous 

concentration. Others, particularly those 

with high melting points, dissolve and 

then rapidly crystallize if they are not 

sustained by the polymer. 

As an example, for a DCS Class IIA 

compound for which amorphous solubility 

is easily sustained, the critical problem to 

solve is getting the compound to rapidly 

dissolve. Often, neutral polymers, such as 

BASF’s Kollidon VA64 (vinyl pyrrolidonevinyl 

acetate copolymers), work well due 

to their high water solubility, ability to 

dissolve in gastric media, and the reduced 

need to sustain the drug concentration. In 

fact, Kollidon VA64 can be highly 

preferred in these cases due to its high 

solubility in organic solvents typically 

used in spray-drying. Higher spray-solvent 

concentrations can substantially improve 

throughputs, which can lead to a decrease 

in the cost of goods. 

For compounds that have a tendency 

to crystallize in solution or the solid state 

and that require improved solubilization, 

enteric, cellulosic polymers, such as Dow 

or Shin Etsu’s hydroxypropyl 

methylcellulose acetate succinate 

(HPMCAS) or Eastman’s cellulose acetate 

phthalate (CAP), perform very well. This 

is due to a combination of factors–one 

being that the high glass-transition 

temperature of the polymers lead to superb 

solid-state stability for the dispersions; the 

second is that both polymers form colloids 

in solution that combine with the drug to

yield both enhanced solubility and rapid 

dissolution rates. 

As with technology, we are not tied to 

the choice of specific excipients, but we 

do find that HPMCAS has led to superior 

performance for more than half of the 

compounds we have worked on. An added 

benefit of formulating with HPMCAS is 

that Bend Research and its clients have 

access to one of the most complete safety 

packages through the Type V drug master 

file (DMF) for this polymer. 

THE FUTURE OF 

SOLUBILIZATION 

TECHNOLOGY 

With BCS Class II compounds 

comprising an increasing percentage of 

compounds in our clients' discovery 

portfolios, Bend Research is positioned to 

continue to provide the highest-quality 

support and innovation for our clients' 

pipelines. This proactive support is 

focused on two crucial areas: (1) support 

of the existing technology platforms and 

(2) development of next-generation 

technologies. 

To support existing technologies, we 

are engaged in ensuring clients have 

seamless access to the spray-drying 

capacity required as their compounds 

advance, as well as ensuring high-quality 

excipient supplies. An example of ready 

client access to spray-drying capacity is 

reflected in our collaboration with 

Hovione. This collaboration allows for 

facile transfer of programs from Bend 

Research’s research and development 

facilities to Hovione commercial facilities, 

either during Phase III clinical trials or 

following product launch. We know from 

experience that each client has preferred 

timing for this transfer, and we work with 

them to identify the best options and to 

perform technology transfer against this 

plan. 

Similarly, we are working with the 

leading excipient providers to ensure 

access to a reliable supply of 

solubilization excipients that meet the 

critical-to-quality properties that are keys 

to their performance. These relationships 

are an active piece of our technologydevelopment 

portfolio and continue to 

mature. 

In addition to supporting the existing 

technologies, Bend Research is working to 

develop new solubilization technologies. 

These efforts include working with the 

excipient providers to develop new 

solubilization excipients that improve 

performance and processability as well as 

developing improved spray-drying 

processes and equipment. 

Finally, in addition to our internal 

research and development efforts and our 

ongoing work with our alliance partners, 

we are actively forming partnerships to 

commercialize the best new solubilization 

technologies in partnership with 

universities and small companies. Based 

on our company’s successful track record 

in advancing numerous technologies and 

reducing them to practice, this work is 

only natural, particularly given the 

increasing number of poorly soluble 

compounds being developed by the 

pharmaceutical industry. u 

Pr 


Dr. Rod Ray is Chief Executive Officer and 

Chairman of the Board at Bend Research, 

where he has worked since 1983. During his 

time at Bend Research, Dr. Ray has held 

numerous positions specializing in the 

development and commercialization of a wide 

range of products. He has been instrumental 

in directing the management of large-scale 

programs to advance pharmaceutical 

compounds through the development process 

to commercialization, serving as the primary 

management contact for client companies. In 

addition to his expertise in advancing 

pharmaceutical processes and products, Dr. 

Ray has extensive experience in 

commercializing diverse products for the 

electronics, energy, medical, agricultural, and 

space industries. He earned his BS in Chemical 

Engineering from Oregon State University, and 

his MS and PhD in Chemical Engineering from 

the University of Colorado - Boulder. He is a 

licensed Professional Engineer in Colorado and 

Oregon. Dr. Ray holds 21 US patents and has 

41 scientific publications to his credit. 


29


30 

TRANSDERMAL 

D E L I V E R Y 

Recent Developments in Microneedle 

Technology for Transdermal Drug 

Delivery & Vaccination 

By: Mikolaj Milewski and Amitava Mitra 

MICRONEEDLE-ASSISTED 

TRANSDERMAL DRUG 

DELIVERY 

Dissolving Microneedles 

These types of microneedles are 

fabricated using biodegradable polymers in 

which drugs or vaccines are encapsulated 

in the microneedles. 5 Once in the skin, the 

microneedles dissolve, thus releasing the 

drug. The enhancement of flux afforded by 

microneedles has generated significant 

interest in this transdermal delivery 

technology for delivery of peptides and 

proteins. Fukushima et al reported using 

two-layered dissolving microneedles for 

transdermal delivery of human growth 

hormone (rhGH) and desmopressin 


The skin has long been recognized as a potential target for local and systemic drug delivery as well as vaccination. The 

practical value of transdermal route of drug administration is, however, limited by substantial barrier properties of the skin. 

Physiologically beneficial protection that the skin provides against xenobiotic permeation is a drawback from the perspective 

of percutaneous transport of therapeutic agents. Thus, a delivery system that temporarily and reversibly permeabilizes the 

skin can enable delivery of a wide spectrum of molecules across the skin. One such technology is microneedles, which are 

micron-scale needles that can create microscopic pores in the stratum corneum and upper layers of the epidermis, thereby 

enhancing skin permeation up to several orders of magnitude. 1 Four designs of microneedles have been developed: dissolving 

microneedles made of biodegradable polymers that encapsulate drugs or vaccines, solid coated microneedles in which the 

drugs or vaccines are coated on the microneedle surface, hollow microneedles for injection, and solid microneedles to pierce 

the skin followed by application of a drug patch (poke and patch approach) (Figure 1). 2 The purpose of this article is to 

highlight some of the recent advances in the field of microneedle-mediated transdermal drug delivery and vaccination, 

including summaries of preclinical pharmacokinetic data and a brief overview of clinical studies. This review encompasses the 

time period from 2010 to present day. For more background on microneedles, interested readers should refer to the following 

references. 3,4 

(DDAVP) in rats. 6 rhGH (22 kDa) was 

formulated at 2-microgram doses in the 

dissolving microneedles composed of 

sodium chondroitin sulfate and dextran. 

The application of this microneedle 

formulation to the rat abdomen produced a 

PK profile characterized by fast attainment 

of peak concentration (t max = 15 mins) and 

gradual decrease in the plasma rhGH level 

with terminal half-life approximating 25 

mins. Chondroitin-based and dextran- 

based microneedles performed similarly. 

Importantly, the authors observed dose- 

proportional increase in C max , and the area 

under concentration-time curve (AUC) as 

a function of dose. Also, the bioavailability 

was very high and amounted to 

approximately 95% in chondroinin 

microneedles and 73% in dextran 

microneedles. Interestingly, the IV bolus 

injection of rhGH revealed much shorter 

elimination half-life (4 mins) implying 

flip-flop kinetics for microneedle-mediated 

delivery. Hence, the terminal half-life of 

25 mins following microneedle application 

was attributed to the absorption rather than 

elimination phase. On the other hand, 

DDAVP (1.07 kDa) chondroitin 

microneedles showed no flip-flop kinetics 

and an absorption phase half-life of 14 

mins. PK profiles were characterized by 

tmax of 30 mins and terminal half-life of 

approximately 2 hrs. Approximately 0.1 

mg rhGH could be formulated into a patch 

of 100 microneedles. The microneedle 

formulations were stable for at least 1


32 

month under refrigeration or freezing 

conditions. 

F I G U R E 1 

A schematic depiction of four basic modes of 

microneedle application in transdermal drug 

delivery: a) poke and patch in which the skin 

is pretreated with microneedles to be 

subsequently covered by a transdermal 

formulation; b) coated microneedles in which 

drug is coated on the surface of the 

microneedles; c) dissolving microneedles in 

which drug is embedded in the matrix of 

dissolving microneedles (typically polymer- or 

sugar-based); and d) hollow microneedles in 

which drug formulation is injected 

intradermally. Reproduced with permission 

from the International Journal of 

Pharmaceutics. 2008;364:227-236. 

An independent, but related, study of hGH 

in rats was carried out by Lee et al. 7 

Carboxymethylcellulose-(CMC) and CMC- 

trehalose-based dissolving microneedles were 

administered to hairless rats reaching C max after 

approximately 30 mins and subsequently, 

plasma concentration decreased gradually with 

a half-life of 1.1 hrs. The authors subsequently 

compared microneedle-mediated hGH delivery 

with subcutaneous (SC) injections 

demonstrating markedly similar PK profiles. 

Another study by Yukako et al reported 

low bioavailability of peptide leuprolide acetate 

(LA, 1.2 kDa) following administration to rats 

by dissolving microneedles and subcutaneous 

injection. 8 In accordance with in vitro release 

data, in vivo PK profiles demonstrated short 

tmax (15 mins) for microneedles and 20 mins 

for SC injection. However, low bioavailabilities 

(32%) were observed due to the metabolic 

instability of LA in skin. This study highlights 

the potential limitations of microneedle- 

mediated drug delivery related to the 

physiology of the skin rather than the 

microneedle technology itself. 

Coated Microneedles 

Daddona et al studied the 

pharmacokinetics and pharmacodynamics of 

parathyroid hormone (PTH, 4.1 kDa) 

microneedle-mediated delivery in humans. 9 

The microneedle arrays consisted of titanium 

microneedles coated with PTH (20 to 40 

micrograms) attached to an adhesive patch. The 

patch is applied with a hand-held and reusable 

applicator. A once-daily subcutaneous injection 

of FORTEO ® , which is used as a therapy for 

advanced osteoporosis in men and post- 

menopausal women, served as a reference for 

the evaluation of the coated microneedle 

system performance with a wear time of 30 

mins. Clinical studies in post-menopausal 

women demonstrated that the microneedle 

system achieved shorter t max of approximately 8 

mins compared to 24 mins for SC injection. 

The terminal half-life after SC injection was 

longer compared to microneedle delivery, and 

implied flip-flop kinetics. The relative 

bioavailability of the PTH microneedle patch 

ranged from 40% to 80%. Interestingly, these 

differences were believed to be dictated by 

application to different anatomical body sites 

and not by the patch performance 

inconsistency, with the highest relative 

exposure that was obtained from the abdomen, 

followed by upper arm, and the lowest from the 

thigh. In each case, the residual PTH found on 

the microneedle array after application was 

< 20%. Dose-proportional increase in the AUC 

was observed in the clinic. The inter-subject 

and between-occasion intra-subject variability 

seen in the PTH-patch and FORTEO were 

comparable. Pharmacodynamically, the PTH- 

coated microneedle produced dose-proportional 

increase in the bone mineral density. The 

magnitude of this effect was higher compared 

to FORTEO and might be related to different 

PK achieved with the application of PTH 

microneedle. Moisture and oxygen-devoid 

packaged PTH microneedle patches were 

found to be stable in room temperature for 2 

years, which is a significant advantage over 

FORTEO that needs to be stored at 5°C to 8°C. 

Another study involving the Zosano 

microneedle patch system was carried out by 

Peters et al. 10 In this study, the stability and 

preclinical performance of erythropoietin- 

coated microneedles (EPO, approx. 34 kDa) 

was evaluated in rats. Pharmacokinetic profiles 

obtained following SC and microneedle- 

assisted administration of EPO were alike and 

resulted in tmax of 6 to 12 hrs and a terminal 

elimination half-life of 9 to 12 hrs. A linear 

AUC dose-response curve was achieved within 

the 7- to 200-microgram dose range tested. 

Moreover, the relative bioavailability of EPO 

after microneedle administration was 

comparable to that obtained following SC 

injection. 

Zhang et al investigated the potential of 

lidocaine-coated microneedles for local 

analgesic action in domestic swine. 11 This 

study was unique because here, an attempt was 

made to use the microneedles to enhance local 

(dermal) delivery of a therapeutic agent. The 

authors used 3M’s 500 micrometer-long solid 

microneedles, termed sMTS, dip-coated with 

aqueous lidocaine (234 Da) solution. The local 

lidocaine concentration, obtained at the 

treatment site immediately following 

microneedle application was higher than the 

estimated level needed for analgesia and was 

maintained for an hour when co-administered 

with vasoconstrictive lidocaine. 

Hollow Microneedles 

Harvey et al investigated microneedlebased 

intradermal and subcutaneous delivery of 

protein drugs in Yucatan minipig. 12 The authors 

employed a single microneedle device for 

injection of insulin and somatropin and a threemicroneedle 

device to inject etanercept in the 

dermal space. In the context of this study, 

microneedle refers to a manually assembled 

complex of 1-mm-long 34-gauge steel needle, 

flexible tubing, and an analytical microsyringe 

drug reservoir. Formulation volumes injected 

intradermally varied in the range of 50 to 250 

microliters. Etanercept (132 kDa) injections 

demonstrated markedly shortened tmax (5 hrs) of

microneedle-mediated delivery as compared to 

18 hrs for subcutaneous injection. The absolute 

bioavailability was 75% for microneedles and 

50% for SC administration. Similarly, 

somatropin (22 kDa) injections showed faster 

absorption kinetics following intradermal 

microneedle-mediated injections (t max = 30 

mins) as compared to subcutaneous 

administration (t max = 2.75 hrs). The absolute 

bioavailability was found to be 100% for both 

routes. Moreover, insulin lispro (5.8 kDa) 

demonstrated rapid uptake to systemic 

circulation when administered intradermally 

(t max = 22 mins) and slower uptake following 

SC injection (t max = 61 mins). Interestingly, the 

absorption rate of regular and fast-acting 

insulin after microneedle-mediated intradermal 

injection was comparable. In all of the 

aforementioned studies, shorter t max was 

accompanied by higher C max . The authors 

performed additional imaging studies that led 

to the hypothesis that rapid uptake seen for 

microneedle-mediated intradermal protein 

delivery is aided by fast lymphatic uptake in 

the dermis. 

Pettis et al studied intradermal 

microneedle delivery of insulin lispro (5.8 

kDa) versus its SC delivery in healthy human 

volunteers. 13 Application of insulin 

intradermally through a single stainless steel 

hollow microneedle and an SC injection 

resulted in rapid systemic absorption and 

bioavailability of microneedle-mediated 

delivery comparable to SC injection. T max 

values increased (36 mins, 40 mins, and 46 

mins) with increasing microneedle length (1.25 

to 1.5 to 1.75 mm) and proved to be the highest 

for SC injection (64 mins). 

Subcutaneous and intradermal delivery of 

liquid formulations through multiple hollow 

microneedles (hMTS, 3M Drug Delivery 

Systems) in domestic swine was studied by 

Burton et al. 14 Pharmacokinetic studies 

compared microneedle-mediated and SC 

administration of three model compounds: 

naloxone (322 Da) hydrochloride, hGH 

(22kDa), and equine tetanus anti-toxin (ETAT, 

approx. 150 kDa). Interestingly, naloxone 

hydrochloride showed faster absorption 

following SC injection compared to 

microneedle administration. In contrast, hGH 

showed faster absorption following 

microneedle administration. The antibody 

(ETAT) showed similar PK profiles with both 

SC and microneedle administration. 

Poke & Patch 

This delivery approach involves piercing 

the upper layers of the skin with solid 

microneedles followed by application of a drug 

formulation (eg, patch, gel) at that site. 2 The 

pretreatment creates microscopic pores in the 

skin, thereby enhancing flux of the molecules. 

Zhang et al reported increased bioavailability 

of L-carnitine (LC) in rats with the poke and 

patch method compared to its oral 

administration. 15 Although LC is a small 

molecular weight compound (161 Da), it does 

not permeate at high rates through intestinal 

epithelium or skin due to its ionized and 

hydrophilic nature. Authors investigated in 

vitro permeation of LC from solution across 

untreated and microneedle pretreated skin and 

demonstrated a 17-fold increase in flux across 

skin pretreated with microneedles. 

Subsequently, several carbomer hydrogels were 

evaluated as formulation options. The CP980 

gel showed an LC transport rate of 72% of that 

of the aqueous solution formulation across 

microneedle pretreated skin. Finally, a rat PK 

study comparing IV, oral, and poke and patch 

delivery methods was conducted. Oral delivery 

of LC resulted in only 8% bioavailability and 

t max of 2 hrs. Following a 6-hr microneedle- 

enhanced transdermal LC delivery, 22% 

bioavailability was achieved with t max at 4 hrs. 

The bioavailability was calculated on the basis 

of the total dose applied in the patch. An 

alternative calculation based on the fraction of 

the total dose that was actually delivered into 

skin yields a bioavailability of 81%. 

Interestingly, the poke and patch PK profile 

resembled a traditional non-microneedle 

percutaneous profile in the sense that relatively 

steady plasma levels were obtained in the 2- to 

6-hr time window. However, the likely reason 

for lack of more pronounced C max is that the 

timeline of the experiment was relatively short, 

and the microchannels did not close enough to 

significantly limit in vivo flux through the 

microchannels. 

F I G U R E 2 

Becton Dickinson's Micro Injection System 

demonstrating: a) microneedle shield; b) 

microneedle pre-attached to the tip of the 

syringe; c) vaccine-level check window; d) 

finger pads; and (e) plunger rod. 

Reproduced with permission from Vaccine 25 

(2007) 8833–8842. 

MICRONEEDLE-ASSISTED 

VACCINATION 

The use of the skin as a target site for 

vaccination has been largely limited due to the 

difficulty in reliably performing intradermal 

injections. With the advent of microneedles, a 

minimally invasive and precise intradermal 

placement of vaccine has become possible. The 

skin is known to be a highly immunogenic 

tissue containing a wealth of antigen-presenting 

cells, including epidermal Langerhans' cells 

and dermal dendritic cells. 16 As such, it is a 

good vaccination target with additional dosesparing 

potential compared to lessimmunogenic 

muscle tissue. 

A recent study by Weldon et al examined 

an influenza vaccine-coated microneedle in 

mice. 17 The authors chose to utilize trehalosestabilized, 

solubilized viral protein antigens 

rather than more widely employed inactivated 

influenza virus and virus-like particles. 

Microneedles coated with stabilized 

recombinant trimeric soluble hemagglutinin 

33 

Drug Development & Delivery July/August 2012 Vol 12 No 6


(sHA) provided superior protection against 

influenza virus compared to the unmodified 

sHA. Moreover, post-challenge lung titers 

demonstrated that intradermal vaccination 

resulted in greater clearance of replicating 

virus compared to the SC vaccination. 

In another study, Kommareddy et al 

investigated the use of dissolvable microneedle 

patches delivering influenza vaccine antigens in 

mice. 18 The authors employed TheraJect TM 

VaxMat TM microneedle technology to 

incorporate microgram quantities of vaccine in 

a microneedle patch. A set of in vitro and in 

vivo studies confirmed the integrity and 

immunogenicity of the antigens incorporated 

into a dissolving microneedle patch. 

However, perhaps most interestingly, 2011 

proved a ground-breaking year for the 

commercialization of microneedle drug delivery 

technologies in the US. On May 9, 2011, the 

FDA approved a first, and so far the only, 

microneedle-based product: Fluzone 

Intradermal ® influenza virus vaccine (Sanofi 

Pasteur). 19 This constituted a major milestone in 

the transition of microneedle systems from the 

developmental stage to the market place. The 

vaccine is administered from a prefilled 

microinjection system consisting of a custom 

syringe with a 30-gauge, 1.5-mm-long, hollow 

single microneedle developed by Beckton 

Dickinson (Figure 2). 20 The microneedle is about 

10 times shorter than a traditional needle used to 

perform intramuscular injections of Fluzone. 

Moreover, Phase III clinical data confirmed that 

intradermal delivery of vaccine allows for dose- 

sparing. A 9-microgram dose of vaccine 

delivered intradermally proved to be 

immunogenetically comparable to a 15- 

microgram dose delivered intramuscularly. 21 

Hence, a 40% reduction in the dose was 

achieved. In 2009, Intanza ® , an influenza vaccine 

based on the same microneedle technology, was 

approved by the European Medicines Agency 

(EMA). 22 These recent developments and the 

appearance of first products on the market have 

encouraged academic institutions and 

pharmaceutical industries to pursue the 

microneedle-based strategy for drug delivery and 

vaccination purposes as reflected by several 

34 

ongoing clinical trials. 

CLINICAL TRIALS INVOLVING 

MICRONEEDLES 

A number of ongoing trails with 

microneedle-based delivery systems illustrate 

the significant interest in this new transdermal 

delivery technology. Several clinical studies are 

listed in ClinicalTrials.gov. 23 A few of the 

notable studies are discussed here. Sanofi 

Pasteur has completed a Phase II trial that 

assessed non-inferiority of fractional doses of 

IMOVAX ® Polio administered intradermally 

versus full doses of IMOVAX Polio 

administered intramuscularly (study results 

pending). Phase II and III studies sponsored by 

Emory University currently investigate the 

difference in glycemic control between the SC 

insulin catheter and microneedle for bolus 

delivery of insulin. NanoPass technologies' 

ongoing studies evaluate the safety and 

efficacy of a MicronJet microneedle device as 

well as safety, pharmacokinetics, and 

pharmacodynamics of insulin injected via 

MicronJet. A Phase II study on 

pharmacokinetics and pharmacodynamics of 

basal insulin infusion administered either 

intradermally or subcutaneously has been 

completed by Becton Dickinson (study results 

pending). Furthermore, a Phase I clinical study 

assessing tolerability of the application of a 3M 

microstructure transdermal system has been 

completed (study results pending). Finally, 

Zosano Pharma microneedle-based PTH patch 

had completed Phase II clinical trials, and the 

results were published and summarized in the 

aforementioned Coated Microneedles section. 

SUMMARY 

Early research in the area of microneedle- 

assisted transdermal drug delivery provided 

ample proof of its potential in enhancing and 

enabling transport of pharmaceuticals across 

thr skin. It also demonstrated its limitations 

related to the relatively small drug doses that 

can be used in conjunction with the 

microneedle technique and the microneedle 

fabrication complexity, including related 

challenges in therapeutic agents' stability. 

Following extensive investigation of 

microneedle fabrication methods, later studies 

focused toward improving the performance of 

existing microneedle systems. Multiple 

preclinical and clinical studies demonstrated 

their successful application in vivo. The 

viability of the microchannels was assessed in 

vivo and its implications for the applicability of 

the poke and patch method were recognized. 

Clinical successes have resulted in significant 

interest from both academia and the 

pharmaceutical industry in this delivery area. A 

selective review of the recent advancements in 

this field reported herein highlights growing 

sophistication of this technology in its ability to 

deliver a wide variety of molecules and 

vaccines with precision. Importantly, at a time 

when biopharmaceuticals (biologics and 

vaccines) are becoming an integral part of 

pharmaceutical pipelines, microneedle-based 

devices offer a promising alternative to 

traditional SC and intramuscular injections.u 

REFERENCES 

1. Henry S, McAllister DV, Allen MG, 

Prausnitz MR. Microfabricated 

microneedles: a novel approach to 

transdermal drug delivery. J Pharmaceut 

Sci. 1998;87(8):922-925. 

2. Arora A, Prausnitz MR, Mitragotri S. 

Micro-scale devices for transdermal drug 

delivery. Int J Pharm. 2008;364(2):227-236. 

3. Sachdeva V, Banga A. Microneedles and 

their applications. Recent Patents on Drug 

Delivery & Formulation. 2011;5(2):95-132. 

4. Donnelly RF, Raj Singh TR, Woolfson AD. 

Microneedle-based drug delivery systems: 

microfabrication, drug delivery, and safety. 

Drug Deliv. 2010;17(4):187-207. 

5. Park J-H, Allen MG, Prausnitz MR. 

Biodegradable polymer microneedles: 

fabrication, mechanics, and transdermal 

drug delivery. J Controlled Rel. 

2005;104(1):51-66. 

6. Fukushima K, Ise A, Morita H, Hasegawa 

R, Ito Y, Sugioka N, Takada K. Two-layered 

dissolving microneedles for percutaneous 

delivery of peptide/protein drugs in rats.

Pharm Res. 2011;28(1):7-21. 

7. Lee JW, Choi SO, Felner EI, Prausnitz MR. 

Dissolving microneedle patch for 

transdermal delivery of human growth 

hormone. Small. 2011;7(4):531-539. 

8. Ito Y, Murano H, Hamasaki N, Fukushima 

K, Takada K. Incidence of low 

bioavailability of leuprolide acetate after 

percutaneous administration to rats by 

dissolving microneedles. Int J Pharm. 

2011;407(1-2):126-131. 

9. Daddona PE, Matriano JA, Mandema J, 

Maa YF. Parathyroid hormone (1-34)-coated 

microneedle patch system: clinical 

pharmacokinetics and pharmacodynamics 

for treatment of osteoporosis. Pharm Res. 

2011;28(1):159-165. 

10. Peters EE, Ameri M, Wang X, Maa YF, 

Daddona PE. Erythropoietin-coated ZP- 

microneedle transdermal system: 

preclinical formulation, stability, and 

delivery. Pharm Res. 2012 [Epub ahead of 

print]. 

11. Zhang Y, Brown K, Siebenaler K, 

Determan A, Dohmeier D, Hansen K. 

Development of lidocaine-coated 

microneedle product for rapid, safe, and 

prolonged local analgesic action. Pharm 

Res. 2011;29(1):170-177. 

12. Harvey J, Kaestner SA, Sutter DE, Harvey 

NG, Mikszta JA, Pettis RJ. Microneedle- 

based intradermal delivery enables rapid 

lymphatic uptake and distribution of 

protein drugs. Pharmaceeut Res. 

2011;28(1):107-116. 

13. Pettis J, Ginsberg B, Hirsch L, Sutter D, 

Keith S, McVey E, Harvey Noel G, 

Hompesch M, Nosek L, Kapitza C, 

Heinemann L. Intradermal microneedle 

delivery of insulin lispro achieves faster 

insulin absorption and insulin action than 

subcutaneous injection. Diabetes Technol 

Therapeut. 2011;13(4):435-442. 

14. Burton A, Ng C-Y, Simmers R, Moeckly 

C, Brandwein D, Gilbert T, Johnson N, 

Brown K, Alston T, Prochnow G, 

Siebenaler K, Hansen K. Rapid 

intradermal delivery of liquid formulations 

using a hollow microstructured array. 

Pharmaceut Res. 2010;28(1):31-40. 

15. Zhang S, Qin G, Wu Y, Gao Y, Qiu Y, Li F, 

Xu B. Enhanced bioavailability of Lcarnitine 

after painless intradermal 

delivery vs. oral administration in rats. 

Pharm Res. 2011;28(1):117-123. 

16. Kupper TS, Fuhlbrigge RC. Immune 

surveillance in the skin: mechanisms and 

clinical consequences. Nat Rev Immunol. 

2004;4(3):211-222. 

17. Weldon WC, Martin MP, Zarnitsyn V, 

Wang B, Koutsonanos D, Skountzou I, 

Prausnitz MR, Compans RW. Microneedle 

vaccination with stabilized recombinant 

influenza virus hemagglutinin induces 

improved protective immunity. Clin 

Vaccine Immunol. 2012;18(4):647-654. 

18. Kommareddy S, Baudner BC, Oh S, Kwon 

SY, Singh M, O'Hagan DT. Dissolvable 

microneedle patches for the delivery of 

cell-culture-derived influenza vaccine 

antigens. J Pharm Sci. 2012;101(3):1021- 

1027. 

19. 2009. FDA Approval Letter - Fluzone 

Intradermal; 

http://www.fda.gov/BiologicsBloodVaccine 

s/Vaccines/ApprovedProducts/ucm255160. 

htm. ed. FDA. 

20. Laurent PE, Bonnet S, Alchas P, Regolini 

P, Mikszta JA, Pettis R, Harvey NG. 

Evaluation of the clinical performance of a 

new intradermal vaccine administration 

technique and associated delivery system. 

Vaccine. 2007;25(52):8833-8842. 

21. 2011. Fluzone Intradermal(R) prescribing 

information; 

https://www.vaccineshoppe.com/image.cf 

m?doc_id=12427&image_type=product_p 

df. ed.: Sanofi Pasteur. 

22. 2009 Intanza market authorisation; 

http://www.ema.europa.eu/ema/index.jsp?c 

url=pages/medicines/human/medicines/000 

957/human_med_000842.jsp&mid=WC0b 

01ac058001d124&murl=menus/medicines/ 

medicines.jsp&jsenabled=true. ed.: EMA. 

23. ClinicalTrials.gov; http://clinicaltrials.gov/. 

ed.: U.S. National Library of Medicine. 

Pr 


Dr. Mikolaj 

Milewski is a 

Senior Research 

Pharmacist at 

Merck. As a 

member of the 

Biopharmaceutics 

group, he 

assesses 

bioperformance 

risk of toxicology 

and clinical formulations. He also evaluates 

feasibility of alternative drug delivery routes 

for new chemical entities and existing 

products. He has authored research and review 

articles in peer-reviewed journals and is a 

member of AAPS and ACS. His areas of interest 

focus on oral and transdermal formulations, 

pharmacokinetics, and development of 

microneedle-based drug delivery systems. Prior 

to joining Merck, Dr. Milewski earned his PhD 

in Pharmaceutical Sciences from the University 

of Kentucky in Lexington. 

Dr. Amitava 

Mitra earned his 

BS in Pharmacy 

from Birla 

Institute of 

Technology, India, 

his PhD in 

Pharmaceutical 

Sciences from the 

University of 

Maryland, and 

completed his post-doctoral fellowship from 

Fox Chase Cancer Center. Dr. Mitra has 

published research articles in peer-reviewed 

journals and has authored review articles and 

book chapters. He has numerous podium and 

poster presentations in national and 

international conferences. He is a member of 

the AAPS, CRS, and the Rho Chi Pharmacy 

Honor Society. He is a recipient of the 

Controlled Release Society-3M Drug Delivery 

Systems Graduate Student Outstanding 

Research Award in 2005 and American 

Association of Pharmaceutical Scientists- 

National Biotechnology Conference Graduate 

Student Award in 2006. 


35


36 

INJECTION 

M O L D I N G 

Injection Molding in the 

Pharmaceutical Industry 

By: Andrew Loxley, PhD, and Brett Braker 

THE MOLDER 

The major components of an 

injection molder are shown in Figure 1. 

The IM process involves four essential 

steps: 

1. Melting of material 

2. Mass transfer of molten material 

from an injector into channels 

called “runners” in the mold and 

finally into the mold cavity 

3. Hardening of the material in the 

mold to the shape of the cavity 

4. Ejecting the part from the cavity 

to produce the final product 

The earliest injection molders used a 

simple piston to force molten material into 

the mold. Modern molders use a combined 

heated barrel/screw/ram assembly in which 

the solid material is fed to the hopper of 

the heated barrel, where it is melted by a 


Many of the processes used to manufacture products within the pharmaceutical industry are unique to the particular 

product; however, there are also processes that have been borrowed and adapted from other manufacturing industries and 

successfully employed in the development of pharmaceutical products. One such example is injection molding (IM); a process 

developed in the late 19th century for the manufacture of simple plastic objects, such as combs, and later extended to all 

manner of parts made from thermoplastic and thermoset resins. Parts made by IM that are widely used in the pharmaceutical 

industry include caps, seals, closures, valves, syringes, inhalers, and the like. As with other plastic processing technologies 

that enable pharmaceutical solutions for otherwise difficult problems, IM is now gaining in popularity for manufacturing 

more complex device parts, and is even the platform of choice for preparing certain proprietary drug products. 

combination of the heat from the heater 

bands and the shear forces between the 

material, screw, and barrel. The molten 

material is conveyed by the screw toward 

the nozzle at the end of the barrel, and the 

screw then travels forward in the barrel as 

a ram to inject the material into the mold 

on each cycle. The addition of the screw 

also allows for some mixing so that 

multiple feedstocks can be added 

F I G U R E 1 

Diagram of basic injection molding machine. 

simultaneously to prepare for example 

colored parts, or to reuse scrap from 

previous runs. Two examples of pilot-scale 

injection molders from Nissei and Arburg 

are shown in Figure 2. AB Insturments, 

Thermo Haake and Alba are among 

makers of lab-scale injection molding 

units. 

Molders can be hydraulic, electric, or 

pneumatic, with electric or pneumatic


38 

being preferred for pharmaceutical applications 

due to the potential issues of clean room 

contamination from hydraulic fluid aerosols. 

IM machines range in sizes from tabletop 

versions making micro-parts a few millimeters 

in size or smaller, to large-scale production 

machines requiring clamp pressures of the 

order of thousands of tons to hold the mold 

halves together during the molding process. 

MATERIALS 

Materials that are solid at room 

temperature must be heated above the meting 

temperature (T m ) before being pumped into the 

mold cavity. The temperature of the 

thermoplastic material needs to be raised 

sufficiently above T m to reduce its melt 

viscosity and allow transfer from its reservoir 

to the mold cavity at manageable pressures. 

The higher the temperature above T m , the lower 

the melt viscosity and hence the lower the 

pressure required to pump the material through 

the runners into the cavity. Of course, elevated 

temperatures accelerate thermal degradation (of 

polymers, additives, and drugs), so the lowest 

temperature that allows for reproducible part 

production should be used. Thermoplastic 

materials with glass transition temperatures 

(T g ) above room temperature form hard parts 

upon cooling, and suitable materials include 

resins, such as polystyrene, poly(methyl 

methacrylate), polypropylene, and 

polyethylene. Thermoplastic materials with T g 

below room temperature (thermoplastic 

elastomers) form rubbery parts on cooling, and 

example materials suitable for IM are ethylene 

vinyl acetate copolymers (EVA, eg, 

VitalDose TM ), various polyurethanes (eg, 

Chronothane TM , Elasthane TM , Tecoflex ® ), 

polystyrene-polyisobutylene block terpolymers 

(eg, Kraton TM ), polyether-polyamide block 

copolymers (eg, Peebax ® ), and polyvinylbutyral 

(eg, Butvar ® ). 

When the material is a liquid at room 

temperature, and cures in the mold by a 

chemical reaction to form the final part, the 

process is called reactive IM (RIM) and is 

exemplified by silicone elastomers in which 

low molecular weight reactive silicone liquids 

are cured in the mold at elevated temperatures 

by Platinum-catalyzed or Tin-catalyzed 

crosslinking reactions. Cycle times are 

typically longer for silicones than for 

thermoplastic products, as the part must cure 

before being ejected from the mold, and this is 

usually slower than simple cooling. 

MOLDS 

Molds are made of metal plates that have 

precision machined cavities in which the part 

cools or cures to take its final form after the 

material is injected into it. At the smallest 

tabletop injection molder scale, molds are 

F I G U R E 2 

Examples of injection molding machines, on the left, a Nissei hydraulic unit, and on the right, an 

Arburg electric unit. 

F I G U R E 3 

mostly made from aluminum to save on costs 

and an example o-ring mold is shown in Figure 

3. Production molds for medical and 

pharmaceutical applications are made of 

stainless steel of appropriate regulatory grade. 

Depending on the size and complexity, the cost 

of molds can range from a few thousand 

dollars and can go up to several hundreds of 

thousands. 

The runners may be embedded within the 

plane of the cavity in the mold and filled with 

polymer from the injection nozzle on each 

cycle. Molten material is distributed to each 

cavity in the mold from the runners. Because 

the cavity is generally not heated, the design is 

A simple aluminum o-ring mold showing both mold halves. The cold-runner that feeds the cavity 

is the channel at the top of the upper-right half.

called a cold-runner mold, and material in the 

cold runner hardens or cures with the part and 

is then removed from the part and discarded as 

scrap or in the case of stable thermoplastic 

formulations, sent to be recycled in a later 

molding run after each cycle. Cold runner 

systems are generally used for applications in 

which materials are inexpensive or when use of 

recycled material is acceptable, as they are less 

expensive than hot runner systems. However, 

materials cannot be reprocessed indefinitely, 

especially if thermally labile, and if thermoset 

materials are used in cold runner molds, the 

material must be discarded. 

Hot runner systems use a heated manifold 

that is fed by the injection nozzle and keeps the 

material molten in the runners in the mold 

frame outside the plane of the cavity. The 

molten material enters the cavity from the 

runners via valve-gates or tips, and there is no 

scrap, so costly raw materials losses are 

minimized. Only the material in the cavity cools 

and hardens on each cycle, and molten material 

for the next cycle is forced into the cavity from 

the hot runners as fresh material is pumped into 

the hot manifold from the barrel nozzle. The 

fact that material remains continuously molten 

in the mold means that thermally sensitive 

materials can be subject to degradation, and the 

volume of hot runners should be kept as low as 

possible (a few cavity volumes at most) to 

F I G U R E 4 

In vitro release of dapivirine from an EVA matrix-type IVR made by injection molding (25 mg 

dapivirine). 

ensure labile material does not have a long 

residence time in the molten state. 

PHARMACEUTICAL PRODUCTS 

BY INJECTION MOLDING 

Simple and complex shapes can be 

produced by IM, and as such, the process is 

used to prepare a wide variety of plastic 

medical device parts from caps, seals, closures, 

syringes, valves, and even implants. All of 

these require formulation of polymers with a 

range of additives, such as colorants, 

antioxidants, fillers, and plasticizers. Many of 

the compounds are pre-prepared by hot-melt 

extrusion, pelletized, and the pellets fed to the 

injection molder to form the part. 

Whereas the halves of a gelatin capsule 

that can be filled with API formulation are 

traditionally made by hardening a gelatin 

solution coated on a shaped metal pin by 

dipping it a into gelatin solution, IM can be 

used to prepare capsules, for example, the 

FlexTab TM technology that Capsugel acquired 

in 2011. 

More recently, IM has been used to 

directly incorporate APIs into shaped plastic 

parts, and hence used to prepare drug products. 

The majority of drug products prepared by IM 

are drug-eluting devices (DED); however, even 

more recently, IM has been used to prepare 

solid oral dosage forms (SOD). IM offers the 

product developer novel delivery features, 

specific shaped-part preparation capability, and 

potential for life-cycle management of APIs. 

Commercial DED prepared by IM include 

intravaginal rings (IVR), and several such 

devices on the market made of silicones 

manufactured using a RIM process. Examples 

of such IVR are FemRing ® , Estring ® , and 

Progering ® for hormone replacement therapy, 

vaginal atrophy, and contraception, 

respectively. These are core-sheath reservoir 

devices in which a drug-loaded silicone core is 

coated with a drug-free silicone sheath to 

regulate the rate of release of API from the 

device, yielding virtually zero-order (constant) 

release kinetics. The sheath is put over the core 

in a second injection molding process, making 

manufacturing quite complex. 

The International Partnership for 

Microbicides (IPM) working with Karl 

Malcolm and David Wolfson at Queens 

University, Belfast, has leveraged silicone 

technology in the development of a simpler 

IVR containing the non-nucleoside reverse 

transcriptase inhibitor dapivirine that does not 

have a rate controlling membrane. 1 This IVR is 

a device to protect women from HIV 

transmission during sexual intercourse with an 

infected partner, and is slated to start Phase III 

clinical trials in 2012. 

The RIM process requires the API and 

any other excipients to be suspended in the 

silicone liquids prior to injection (silicones are 

poor solvents so all added materials are 

suspended). Challenges arise from aggregation 

and settling of particulate materials in these 

fluids, which can cause inhomogeneities and 

nozzle blocking. 

Particle Sciences uses IM in the 

development of EVA and polyurethane DED 

for a variety of clients. 2,3 EVA and 

polyurethanes are thermoplastic polymers, and 

APIs and additives can be co-mixed uniformly 

with it prior to IM using hot-melt extrusion to 

yield pellets that are stable and can be used 

right away or stored for later IM processing. 

IVRs are developed first at laboratory scale 

using a bench-top molder, and successful 

formulations are then scaled to larger molding 

units for clinical and then commercial process 

development. The in vitro release of dapivirine 


39


40 

Schematic of the Egalet process. 

from an EVA IVR made by molding 

dapivirine-loaded pellets (1.3% w/w API) in a 

mold with a torroidal cavity is shown in Figure 

4 orange markers), along with the drug-release 

profile fitted using a proprietary predictive 

model (blue line) showing excellent fit to the 

data. The diffusion coefficient of dapivirine in 

EVA can be determined from these plots, 

which in turn allows the prediction of release 

profiles from EVA IVRs of different strengths 

to be made. 

The shape of the curve is typical of 

release from monolithic devices that do not 

have release-rate controlling membrane, such 

as the aforementioned silicone IVR, according 

to Fick’s law for diffusion modified for the 

geometry of the part. 4 Such products are 

appropriate when a high release on day 1 of 

use compared to later time points is acceptable 

or desired. 

Very small shaped parts can be made by 

IM. For example, punctual plugs - small 

polymer pieces shaped to fit into the orifice 

through which tears drain (the puncta) - are 

used in the treatment of dry eye and other 

diseases of the eye. They can be pure polymer 

or medicated with API. In either case, they are 

prepared by micro-injection molding. 

Researchers at the University of Ghent in 

Belgium, have used IM to prepare API-loaded 

tablets for oral sustained release. 5 For example, 

metoprolol tartrate (MPT) was formulated into 

a mixture of polyethylene oxide (PEO) and 

ethyl cellulose (EC). The formulations were 

injection molded into biconvex tablets using a 

Haake MiniJet TM lab-scale injection molder, 

and the in vitro release profiles of the 

MPT/PEO/EC tablets were compared to 

compression molded tablets. The workers 

F I G U R E 5 

found a more sustained-release from the 

injection molded tablets. 

The Danish pharmaceutical company 

Egalet developed a two-step IM process to 

prepare oral dosage forms. The first step 

involves molding an open-ended “tube” of 

non-degradable polymer into which a 

thermoplastic API/polymer formulation is 

molded in a second step. 6 Drug is released by 

erosion from the open ends. The process is 

illustrated in Figure 5. 

SUMMARY 

Injection molding is a versatile process 

that has been in use in plastics processing for 

more than a century. More recently, it has been 

used in the pharmaceutical industry to prepare 

products from medical devices to complex 

controlled-release dosage forms for both oral 

and implantable routes of administration. u 

REFERENCES 

1. Malcolm RK, Edwards KL, Kiser P, Romano J, Smith TJ. Advances 

in microbicide vaginal rings. Antiviral Research. 2010;88[Suppl 1, 

S30-9]. 

2. Clark MR, Kiser PF, Loxley A, McConville C, Malcolm RK, 

Friend DR. Pharmacokinetics of UC781-loaded intravaginal ring 

segments in rabbits: a comparison of polymer matrices. Drug 

Delivery Translational Research. 2011;1(3):238-46. 

3. Loxley A, Gokhale A, Kim Y, McConnell J, Mitchnick M. 

Ethylene-vinylacetate intravaginal rings for zero-order release of an 

antiretroviral drug. Poster presented at the CRS annual meeting in 

NYC; 2008. 

4. Siepmann, Siepmann. Modeling of diffusion controlled drug 

delivery. J Controlled Release. (2011) in press. 

5. Quinten et al. Development and evaluation of injection-molded 

sustained-release tablets containing ethylcellulose and polyethylene 

oxide. Drug Development and Industrial Pharmacy. 

2011;37(2):149-159. 

6. See http://www.egalet.com/index.dsp?area=32. 

Pr 


Dr. Andrew 

Loxley is 

Director of New 

Technologies at 

Particles Sciences 

Inc., a contract 

research 

organization in 

Bethlehem, PA, 

specializing in 

pharmaceutical formulation development. He 

leads a variety of projects, based on novel and 

proprietary nanotechnologies and combination 

devices, in fields from HIV vaccine and 

microbicide development, to gene-silencing 

SiRNA delivery. Prior to joining Particles 

Sciences, he led development efforts in nextgeneration 

lithium ion batteries at A123 

Systems Inc, electrophoretic displays at EINK 

Corp., and emulsion polymers at Synthomer 

Ltd. British-born, he earned his BSc in 

Chemistry from the Univeristy of Sussex and 

his PhD in Physical Chemistry focusing on 

microencapsulation from the University of 

Bristol. 

Brett Braker is 

a Formulator at 

Particle Sciences, 

focusing on the 

development of 

drug-eluting 

devices. He earned 

his BS in Plastics 

and Polymer 

Engineering 

Technology from Pennsylvania College of 

Technology.

MATHEMATICAL 

M O D E L I N G 

Mathematical Modeling for Faster 

Autoinjector Design 

By: Jonathan Wilkins, PhD, and Iain Simpson, PhD 


There is an increasing demand for 

advanced injection devices that bring 

benefits around self-administration and 

ease of use and work with new biological 

drugs, which are often required to be 

delivered in larger volumes and/or at 

higher viscosities than those for 

conventional drugs. In order to reduce 

development and manufacturing costs, 

there is also a desire for platform 

devices, which can meet a broader range 

of drug and user requirements through 

simple adaptation of a core design. 

Unfortunately, a number of devices 

currently in the market do not meet these 

requirements and furthermore, there is 

often a lack of a detailed understanding 

of how the key design parameters affect 

the overall device performance. In some 

cases, this has led to product recalls and 

in other cases, resulted in challenges in 

adapting the designs to meet new needs. 

Hence, there is a commercial need in the 

injectables industry for better 

understanding of how design 

fundamentals affect the performance of 

autoinjector devices. 

Cambridge Consultants believe a 

fast and effective approach to a better 

injection device design is a novel 

combination of mathematical modeling 

on a desktop PC, and complementary 

experimental data. The use of 

mathematical modeling gives insight into 

the physical behavior of the device, and 

allows rapid prediction of the effect of 

different parameters during the design 

process. The more established 

experimental approach provides 

confirmatory data to support the 

modeling. Cambridge Consultants has 

deployed this methodology in a number 

of development projects and achieved 

benefits in terms of reduced 

development time, more robust and 

Schematic of the Autoinjector 

F I G U R E 1 

adaptable designs, and reduced product 

cost. 

Mathematical modeling allows for 

quick simulations of device performance. 

The effect of important design 

parameters, such as injection time, 

injection force, and shear stress on the 

drug, can be predicted in real-time. This 

allows the engineer to investigate the 

design space and quickly optimize a 

suitable set of components for a new 

injection device. For example, the 

mathematical model can guide the 

designer in choosing the correct driving 

spring, needle gauge, and plunger in 

order to meet the device performance 


41


42 

specification. 

In this paper we present a mathematical 

model of device performance applied to a 

typical autoinjector. This has the generic 

features of an autoinjector, but is not tied to 

any specific commercial device, and thus, 

can be tailored to investigate a wide range of 

interesting design features. The approach and 

the type of physics used inside the model are 

described. How experimental data can be 

used to calibrate and verify the model is also 

shown. 

As a case study, we use the 

mathematical model to predict the effect 

needle tolerances have on injection times 

within an autoinjector. This is an essential 

piece of performance data and is something 

that would take weeks and an expensive 

budget to determine experimentally, but that 

can be done in a few hours with a 

mathematical model. 

THE AUTOINJECTOR MODEL 

The generic autoinjector shown in 

Figure 1 and considered for the model has 

the following components, which are 

commonly found in most commercial 

devices: 

• A syringe containing the drug 

• A needle 

• A compliant plunger to seal the drug 

into the syringe 

• A drive spring as the energy source 

that powers the plunger 

• A liquid drug 

• An air bubble between the drug and 

the plunger 

Easy-to-Use GUI for the Model 

The trigger that activates the 

autoinjector by releasing the spring force on 

to the plunger has not been considered. The 

physics of each component can be considered 

in isolation using ordinary differential 

equations that vary with time. 

The needle is modeled as a component 

that creates viscous pressure losses via the 

Hagen Poiseuille equation and inertial 

Drug Shear Strain Rate Predictions 

F I G U R E 2 

F I G U R E 3 

pressure losses at the entry and exit. The drug 

is modelled as a Newtonian fluid. The 

plunger is modelled as a rubber component 

with linear compliance, subject to a 

maximum compression limit. The syringe 

exerts a frictional force on the plunger. For 

the purpose of the model, a 1 ml BD Hypak 

syringe was used as a representative 

commercially available syringe. The air

Injection Time Sensitivities to Needle Tolerances 

bubble is modelled as a compliance, with an 

internal pressure related to the amount of 

compression via Boyle’s Law. The spring is 

modelled as a linear compression spring; it is 

initially compressed and expands during 

device activation. It would be a relatively 

minor change to the mathematical model to 

replace the mechanical spring with a motor 

energy source as used in electronic 

autoinjectors like the EasyPod. 

F I G U R E 4 

F I G U R E 5 

Experimental & Simulated Plunger Forces for a Verification Test Case 

The individual equations describing 

each component are assembled into a 

mathematical model of the entire autoinjector 

system, where all the components are 

interdependent. We use the Simulink 

commercial package to solve this system of 

equations. To make the model user friendly 

for a wide audience, we built a front-end 

GUI in Matlab. As shown in Figure 2, the 

GUI allows for key design parameters to be 

changed easily, has a graphical representation 

of the syringe plunger motion, and also plots 

out metrics of interest such as plunger 

motion, drug pressure, and percentage of 

drug delivered as a function of time. 

The model allows us to look at the 

physical behavior of the autoinjector at 

various points in time. Some of the 

parameters we predict are easy to calculate 

mathematically but difficult to monitor 

experimentally: for instance, shear stress on 

the drug. However, knowledge of the shear 

stress on the drug is important because high 

levels of shear stress can damage and 

degrade the molecules within the drug: 

particularly newer biologic drugs consisting 

of complex chains of proteins. An example 

shear stress simulation is shown in Figure 3 

for a drug with viscosity 6 times greater than 

water that is being driven by a spring with 

stiffness of 600 N/m with either a 27-gauge 

or a 25-gauge needle. Initially, the shear 

stress is several orders of magnitude higher 

than the steady state value. This is due to the 

impact of the initial spring release that causes 

rapid compression of the bubble, and 

subsequent high driving pressures and 

velocities for the drug in the needle. It is 

found that that the smaller diameter 27-gauge 

needle has a peak shear strain rate 

approximately 50% higher than for the 25 

gauge. 

The model also highlights the 

sensitivities in the autoinjector design. For 

example, consider the effect of needle 

diameter ±5% tolerances (nominally 27 

gauge) and needle length ±5% tolerances 

(nominally 0.5 inch) on the time to deliver 1 

ml of drug with a viscosity equivalent to 

water. Injection time is an important metric 

because the patient will prefer a shorter 

duration injection rather than a long one. 

The contour plot in Figure 4 predicts 

that injection time is much more sensitive to 43 

Drug Development & Delivery July/August 2012 Vol 12 No 6


needle diameter than to needle length. A 

difference of 23% in injection time results 

from changing the needle diameter by only - 

5% to +5% of nominal. This knowledge 

allows the designer to focus on the needle 

diameter as the single most powerful design 

parameter that can be used to adjust injection 

time. 

A designer may have to adjust the 

design to compensate for changes in the drug 

formulation. This is particularly true for 

platform devices in which a standard 

mechanical layout is customized to suit a 

range of different drugs. The mathematical 

model can be used to predict how the design 

must be altered to cope with a change in drug 

properties such as viscosity. 

For instance, suppose an initial version 

of the device platform is developed to work 

with a viscosity equivalent to water (1 

centiPoise) and has an injection time of 1.6 

seconds. This is achieved by using a spring of 

stiffness 600 N/m. If a new drug formulation 

has a viscosity that is five times higher (5 

centiPoise), and there is a requirement that 

the injection time should remain constant, the 

model predicts that to achieve this, a spring 

stiffness of approximately 1250 N/m will be 

now be required. This analysis takes minutes 

to perform with the mathematical model, but 

would require a lengthy program involving 

many different mechanical prototypes to do 

experimentally. Having determined the 

required higher spring force, the rest of the 

design can then be re-evaluated and modified 

if necessary to ensure it can function with the 

stiffer spring. 

EXPERIMENTAL VERIFICATION 

It is important to be able to confirm that 

the underlying equations representing each 

component in the model are realistic, and that 

44 

Monte Carlo Tolerance Analysis Predictions 

the output from the mathematical model can 

be trusted. A way to verify the model is to 

compare it with experimental data of the 

force required to drive the plunger on a 

representative commercially available 

syringe. The measurements were made on a 

Mecmesin force-displacement tester, which 

drives the syringe plunger at constant 

velocity and records the required force. This 

is a slightly different scenario from the 

original mathematical model in which a 

known force from the spring is applied and 

the velocity of the plunger is calculated. 

Thus, a modified version of the mathematical 

model was developed specifically for 

verification in which the velocity of the 

plunger is specified and the plunger force is 

calculated. The verification model was 

compared against various different 

experimental test cases. A sample 

verification of the plunger force 

mathematical model predictions and 

measurements is given in Figure 5 for a test 

case with a 2.5-mm long air bubble in a 1-ml 

syringe, a 30-gauge needle, and a test liquid 

six times more viscous than water. 

Predictions and measurements are in good 

agreement. 

F I G U R E 6 

CASE STUDY: MANUFACTURING 

TOLERANCE ANALYSIS 

A common problem in injection device 

development is to understand the effects of 

manufacturing tolerances on the design. The 

designer must ensure the device performs 

within specification over the range of 

component tolerances, whilst considering that 

relying on excessively tight manufacturing 

tolerances can make a design uneconomic. 

We can apply the mathematical model to 

predict the sensitivities of an autoinjector to 

realistic manufacturing process tolerances to 

see whether a design will always perform to 

specification. 

For example, the mathematical model 

can be used to aid the designer in 

understanding how differences in spring 

stiffness or shape arising from production 

variations might affect drug delivery 

performance. For example, for a 5-centiPoise 

formulation, a 10% reduction in spring force 

from 1250 N/m increases injection time by a 

similar percentage, thus the dependence is 

not so critical. 

As another example, consider a device 

with a 1-ml BD HyPak syringe with a

nominal 27-gauge needle of 0.5-inch length, 

and investigate the effect of tolerances on 

injection time. We assume that each needle 

diameter, needle length, and syringe diameter 

vary with a process variation of Cp = 1.33. 

Using a Monte Carlo approach, we 

simulate a sample of 1000 syringes that 

embody this distribution of tolerances, and 

the results are shown in Figure 6. The 

mathematical model is run once for each of 

these syringes, and the injection times are 

predicted. This takes a matter of hours. Doing 

this experimentally would take weeks, and 

would require a lot of test specimens to be 

made at representative tolerances that would 

be expensive. 

This Monte Carlo approach is more 

realistic and offers a narrower range of 

injection times than a simpler worst case 

tolerance analysis in which all tolerances are 

assumed to be at the maximum permissible 

extremes. Our combination of the 

mathematical model with a Monte Carlo 

approach means the designer has a more 

realistic knowledge of the effects of 

tolerances and can make statements, such as 

“90% of all devices will have an injection 

time between 1.5 and 1.9 seconds.” That the 

real distribution of tolerances are narrower 

than the worst case values means the 

designer can achieve a given outcome and 

still specify less-restrictive tolerances in the 

manufacturing processes. This will result in 

considerable cost savings, particularly with 

an autoinjector that is likely to be made in 

quantities of millions per year. 

SUMMARY 

This article has introduced a 

mathematical model of an autoinjector. The 

fundamental approach considers the generic 

physical features of a device, and can be 

tailored to model specific commercial 

products as required. The model has been 

written in the commercial package Simulink 

to make it quick to adapt and to run. 

Simulink solves the detailed mathematics 

describing the physics of the device. To make 

the model intuitive and easy to use, we 

created a graphical user interface, which 

means it is accessible to designers who do 

not necessarily need to know the specifics of 

the physics behind the device. 

We have shown how the model can be 

used at the early design stage to define key 

components, such as the drive spring or 

needle in order to meet the product 

requirements specification. The model also 

facilitates platform solutions by allowing the 

designer to predict rapidly the changes 

needed in an existing device to meet a 

change in drug specification. Much of the 

behavior the model can predict is difficult to 

measure experimentally, such as shear stress 

in the drug or behavior over short timescales, 

but gives valuable insight into how the device 

functions. The model is also valuable during 

the manufacturing scale-up process, as it uses 

a Monte Carlo approach to simulate the 

effect of tolerance interactions on device 

performance. This is particularly expensive to 

do experimentally, as it would require a large 

range of samples to be manufactured and 

tested. 

We believe more extensive use of 

mathematical modelling in combination with 

experimental testing throughout the 

development process can lead to more robust 

platform injection devices hence reducing the 

risk of product recalls and allowing more 

reliable and cost-effective adaption of device 

designs for the delivery of new therapies. u 

Pr 


Dr. Jonathan 

Wilkins led 

a range of 

drug delivery 

device 

developments 

as Senior 

Consultant at 

Cambridge 

Consultants: 

from inhalers 

through to novel injection systems. He 

has an interest in applying mathematical 

modelling techniques to speed up the 

development and optimization times of 

new products. He has an engineering 

degree and PhD from Imperial College, 

University of London, specializing in fluid 

mechanics. He is currently Qualification 

Manager at Magma Global, developing 

novel materials and processes for the oil 

and gas industry. 

Dr. Iain 

Simpson is 

Associate 

Director of 

Drug Delivery 

in the Global 

Medtech 

Practice at 

Cambridge 

Consultants. 

He has a 20year 

track record of multidisciplinary 

technology and product development, the 

last 12 of which have been spent mainly 

in drug delivery covering parenteral, 

pulmonary, nasal drug delivery as well as 

more invasive device technology of which 

he has mainly worked in program 

management and review roles. He has 

written and presented papers on a range 

of drug delivery topics, including 

developing inhalers for children, 

technology licensing, improving device 

compliance, and usability. He also 

lectures on drug delivery to the 

Cambridge University Masters in 

Bioscience Programme and is a past 

Chairman of the R&D Society. 

Dr. Simpson can be reached at 

iain.simpson@cambridgeconsultants.com 

and to whom correspondence should be 

addressed. 


45


46 

PULMONARY 

D E L I V E R Y 

A Next-Generation Inhaled Dry Powder 

Delivery Platform 

By: Jean C. Sung, PhD 

PRESSURIZED METERED DOSE 

INHALERS (PMDIS) 

Pressurized metered dose inhalers 

(pMDIs) contain drug suspended or 

dissolved in a volatile propellant that is 

atomized for inhalation. The propellants 

that were originally used, 

chlorofluorocarbons and 

hydrofluoroalkanes, emit environmentally 

unfriendly gases. Moving away from these 

propellants has proven to be difficult with 

certain drugs and formulations, reducing 

the number of therapeutics that can be 

formulated in this way. pMDIs are also 

characterized by low lung deposition 

efficiency and require breath coordination 

for effective delivery. 


Drug developers have long sought effective pulmonary delivery of therapeutics to treat diseases inherent to the 

respiratory tract. Indeed, inhaled therapies are certainly favored over oral or intravenous therapies for respiratory and other 

diseases. Pulmonary drug delivery offers superior direct targeting to the site of action, higher lung doses, and lower systemic 

drug concentrations, opening the potential for higher therapeutic index with an overall benefit of lower total body dose and 

reduced potential for adverse events. 1 Delivery of drug to the deep lung can also offer improved access to the systemic 

circulation with several advantages, including rapid onset of action, avoidance of first-pass metabolism, and convenience as 

compared to injection. 

Traditional inhaled drug delivery has used a number of technologies, including pressurized metered dose inhalers 

(pMDIs), nebulizers, and dry powder inhalers (DPIs). While delivery of drugs via these first-generation inhaled drug systems 

provides great advantages over oral or intravenous delivery, these systems also have inherent limitations. The limitations of 

these systems create a tremendous opportunity for next-generation inhaled delivery platforms that can overcome the 

shortcomings of today’s approaches. 

NEBULIZERS 

Nebulizers deliver atomized aqueous 

drug solution by air jet or ultrasonic 

mechanisms. Nebulized drugs are typically 

delivered continuously over multiple 

breaths. Used mostly for elderly, infant, or 

critically ill patients, nebulization is 

typically considered to be a lessconvenient 

delivery system in terms of 

portability and delivery time, and is also 

characterized by low lung deposition 

efficiency. Nebulizers possess limitations 

in terms of the formulation of drugs that 

are degraded by shear and air-water 

interfaces. 

DRY POWDER INHALERS 

(DPIS) 

Dry powder inhalers (DPIs) have 

traditionally used micronized powdered 

medication blended with a large quantity 

of lactose-based carrier, limiting the 

amount of drug that can be delivered. With 

no propellant, DPIs generally rely on the 

force of patient inhalation for delivery, 

which has limited their use in patient 

populations with potentially compromised 

lung capacity, such as children and the 

elderly. These lactose blends are typically 

composed of more than 80% to 90% 

lactose with microgram quantities of drug, 

resulting in a low drug mass-to-volume of 

powder ratio that limits their use primarily 

to high-potency drugs. These powders are 

also generally highly flow rate-dependent 

with respect to their dispersibility, have


48 

poor delivery efficiency with typically less than 

20% of drug making it to the lung, and have 

high patient-to-patient variability. Second- 

generation DP delivery based on particle 

engineering approaches (rather than active 

devices) have included production of porous 

particles and coating of particles with 

hydrophobic force-modifying excipients, such 

as magnesium stearate. Porous particles allow 

for aerosolizable powders with good 

dispersibility over a wide range of inspiratory 

flow rates, however, the inherent low particle 

density results in a low drug mass-to-volume of 

powder inhaled. The reduction in amount of 

drug per unit volume can make porous 

particles unsuitable for large molecule drugs or 

drug combinations that often require higher 

effective drug mass loadings per dose. 

Limitations of existing inhaled drug 

delivery methods have created the opportunity 

for a new approach to DP inhaled drug delivery 

technology. Moving forward, trends in the 

industry indicate that this significant 

opportunity is growing as more pharmaceutical 

and biopharmaceutical companies pursue the 

following product and formulation objectives: 

• using pulmonary delivery for a range of 

small-to-large drug molecules, spanning 

both existing and new drug entities; 

• increasing the dosage of active drug 

F I G U R E 1 

Scanning Electron Micrograph of iSPERSE Particles 

(scale bar presents 2 microns). 

molecules in inhaled therapeutics, 

specifically increasing the drug mass to 

inhaled volume; 

• seeking to commercialize drug 

combination formulations, including 

two, three, and higher numbers of drugs 

combined into a single inhaled product; 

and 

• pursuing reproducible delivery across a 

range of patient populations, including 

pediatrics, the elderly, and those with 

generally compromised lung function. 

A new dry powder formulation approach 

has been developed that overcomes the 

limitations of traditional inhaled delivery and 

has the potential to expand therapeutic options, 

disease targets, and patient populations for 

pulmonary drug delivery. 

NEW PLATFORM FOR DPI 

THERAPEUTICS ADDRESSES 

LIMITATIONS, BROADENS SCOPE 

Based on research to address the 

limitations of existing inhaled dry powder 

formulations, Pulmatrix has developed 

iSPERSE TM , a novel, proprietary inhaled dry 

powder delivery platform for use in the 

pulmonary delivery of drugs. iSPERSE 

particles can be engineered for localized 

therapeutic applications in the lungs, or for 

systemic delivery of therapeutics in which the 

goals include rapid onset of action, avoidance 

of first-pass metabolism, and convenience as 

compared to injection. 

iSPERSE powders are characterized by 

small particle size, relatively high density and 

flow rate-independent dispersibility, along with 

the ability for low or high drug loading of 

single or multiple drugs. iSPERSE represents a 

next-generation pulmonary delivery platform 

with significant potential as iSPERSE’s 

properties yield drug delivery capabilities 

superior to (and indeed not feasible with) 

conventional dry powder technologies that rely 

on the use of lactose blending or low-density, 

porous particles. 

Pulmatrix, a clinical-stage biotechnology 

company discovering and developing a new 

class of therapies for respiratory diseases, 

developed this new approach to inhaled drug 

delivery as part of the development process for 

the company’s own novel, proprietary inhaled 

medicines, some of which are already in 

human clinical trials for a range of diverse 

diseases, such as asthma and chronic 

obstructive pulmonary disease (COPD). 

CUSTOMIZABLE DRUG-TO- 

CARRIER VOLUME 

iSPERSE uses proprietary salt-based 

formulations optimized for inhalation to create 

a robust and flexible platform that can 

accommodate low or high drug loads of a 

range of molecule types. iSPERSE particles 

(Figure 1) are routinely prepared by a singlestep 

spray-drying process from either aqueous 

or organic systems. Small hydrophilic, small 

hydrophobic, and large molecules have all been 

incorporated successfully into iSPERSE 

formulations. These iSPERSE powders can 

contain as little as 5% excipients, which 

compares favorably to the greater than 80% to 

90% lactose that is typical of commercial 

lactose blend DPI formulations. 

This fundamental formulation difference 

of iSPERSE, along with the powder property 

of relatively high density, maps directly into 

drug dose, creating feasible drug doses in a

unit of up to 100 mg for iSPERSE. 2 

Additionally, iSPERSE inherently offers the 

potential of a strong safety profile, as, in 

addition to drug molecules, iSPERSE dry 

powders exclusively contain excipients that are 

generally regarded as safe (GRAS). 

DYNAMIC FLOW RATE EFFICACY 

iSPERSE powders allow for the highly 

efficient delivery of reproducible aerosols to 

the lungs with mass median aerodynamic 

diameters (MMAD) typically ranging from 2 to 

5 microns and respirable fine particle fractions 

routinely greater than 50%. The iSPERSE 

particles also possess the desirable property of 

being highly dispersible across a wide range of 

dispersion energies in spite of their small 

geometric particle size. Across flow rates from 

15 through 60 liters per minute (LPM), the 

percent of powder emitted from a passive dry 

powder inhaler (DPI) using iSPERSE 

formulated DPs is high and remains primarily 

unchanged (Figure 2), delivering drugs to the 

lung much more efficiently and with far less 

energy on the part of the patient. 

iSPERSE powders improve upon the 

delivery efficiency limitations of lactose 

blends, in particular allowing for a reduction in 

nominal dose. This expands the potential 

therapeutic applicability of iSPERSE as it 

could be appropriate for the broadest patient 

populations, including effective inhaled drug 

delivery to patients with normal or impaired 

lung function, using simple and convenient 

commercially available inhaler devices, such as 

passive capsule or blister-based DPI devices. 

Furthermore, iSPERSE formulations can be 

readily made in both clinical trial and 

commercial quantities using the proven and 

scalable spray-drying process capable of high 

and consistent yields. 

MULTI-DRUG COMBINATIONS 

The properties of iSPERSE have 

meaningful therapeutic and patient benefits, 

including the potential for single formulations 

that contain multiple drugs. In fact, preclinical 

data have shown the potential of the iSPERSE 

platform to enable the aerosol delivery of drug 

combinations that include triple drug 

combinations or higher. For example, in in vitro 

and preclinical studies presented recently, an 

iSPERSE fluticasone and salmeterol 

combination was matched to commercially 

available Advair ® Diskus ® , which contains the 

fluticasone and salmeterol combination 

blended with lactose to enable pulmonary 

delivery. 3 A triple iSPERSE combination of 

Advair components and an additional 

anticholinergic bronchodilator was also 

demonstrated. Highlights from these data 

include: 

• iSPERSE demonstrated improved 

delivery efficiency over Advair 

Diskus, as iSPERSE was shown to 

deliver over 2 times more lung 

dose of the active pharmaceutical 

ingredients than Advair Diskus. 

This improved delivery efficiency 

may offer two primary benefits: 

reduced off-target drug exposure 

and oral deposition, which 

potentially could reduce side 

effects such as thrush (oral 

candida) and other infections and 

reduced nominal dose (dose 

sparing), which lowers cost of 

goods. 

F I G U R E 2 

iSPERSE powders are relatively flow rate independent and possess properties suitable for aerosol 

delivery. Two different iSPERSE powder formulations (A, B) exhibited consistent iSPERSE properties of 

being geometrically small, dispersible, and aerodynamically suitable for lung delivery. Capsuleemitted 

powder mass (CEPM) and volume median diameter (VMD) of iSPERSE powders emitted from 

a RS01 DPI as a function of flow rate and measured by laser diffraction (mean ± SD; n = 4-5). 3 

• iSPERSE showed flow rate-independent 

performance in terms of dose and 

particle size distribution, which could 

enable iSPERSE applicability across a 

broad range of patient populations, 

expanding applications beyond patients 

with normal lung function to also 

include those having lower or impaired 

lung function, including pediatric, 

elderly, and those with compromised 

lung function. 

• The iSPERSE particle size distribution 

that would reach the lungs is 

consistent with an Advair Diskus 

particle size distribution (MMAD 

between 3.1 and 3.2 microns for 

iSPERSE comparable to 3.0 microns 

for Advair Diskus). 

• iSPERSE showed excellent agreement 

in size distribution for both drugs 

(fluticasone and salmeterol) and, even 

with the addition of a third drug, 

iSPERSE was able to maintain 

comparable size distribution, flow rate 

independence, and other powder 

properties desirable for inhaled delivery. 

• Consistent delivery of dual and triple 

combination components was achieved, 

with all components of iSPERSE in 

both dual and triple combinations 

retaining expected in vivo activity, as 

demonstrated by reduced lung 

inflammation and airway hyper- 


49


50 

responsiveness in a murine model of 

allergic asthma. 

INHALED DELIVERY OF DIVERSE 

CLASSES OF DRUGS 

The potential of iSPERSE technology has 

been validated not only with small molecule 

drugs, but also macromolecule drugs (proteins, 

peptides, antibodies) at therapeutically relevant 

doses well in excess of those achievable by 

traditional dry powder lactose blend 

technologies. In vivo efficacy has been 

demonstrated with small molecules for the 

treatment of asthma and COPD, antibiotics in 

mouse models of bacterial infection, as well as 

lung and systemic delivery of macromolecules. 

POTENTIAL APPLICATIONS 

FOR ISPERSE 

The attributes of iSPERSE give this 

proprietary novel delivery platform the potential 

to (1) deliver high drug payloads, (2) deliver low 

potency drugs, (3) offer flexible formulation 

options, (4) reduce side effects, (5) facilitate 

straightforward manufacturing, (6) support the 

formulation of small and large molecule drugs 

(proteins and peptides), and (7) support drug 

combinations (including triple drug 

combinations or higher). 

Expanding the viability of dry inhaled 

powder delivery beyond select small molecules 

to include proteins, peptides, and antibodies at 

therapeutically relevant doses as well as triple, 

quadruple, or higher drug combinations will 

enable development of simple, convenient 

inhaled therapies for a new and expanded range 

of disease targets and patient populations. As 

such, iSPERSE has the potential to be the 

pulmonary delivery platform of choice for a 

number of first-in-class and best-in-class inhaled 

therapeutics. 

Commercially, Pulmatrix is seeking 

iSPERSE partnerships as well as advancing its 

own iSPERSE-based drug formulations. In 

terms of diseases that are likely near-term 

candidates for iSPERSE clinical initiatives, a 

number of proprietary iSPERSE drug 

formulation candidates are now being advanced, 

including small molecules, combinations, and 

biologics in a variety of therapeutic areas, 

including COPD, cystic fibrosis, asthma, 

idiopathic pulmonary fibrosis (IPF), and non-CF 

bronchiectasis. 

To support the development of its own 

pipeline as well as the iSPERSE partnering 

programs, Pulmatrix has developed a complete 

range of pulmonary drug formulation 

capabilities that are integral to the successful 

commercialization of the iSPERSE platform, 

including: 

• dry powder formulation and 

manufacturing, 

• dry powder physicochemical properties 

optimization, 

• aerosol characterization and method 

development, 

• dry powder inhaler selection and testing, 

• preclinical efficacy/safety testing (in 

vitro and in vivo), and 

• clinical program operation and 

management. 

These platform and formulation 

optimization capabilities will be offered to 

iSPERSE partners. u 

REFERENCES 

1. Patton and Byron, Inhaling medicines: delivering drugs to 

the body through the lungs. Nature Reviews Drug 

Discovery, 2007;6:67-74. 

2. Sung et al. iSPERSE TM : formulation and in vitro 

characterization of a novel dry powder drug delivery 

technology. Respiratory Drug Delivery Europe. 2011;2:411- 

414. 

3. Sung et al. Pulmonary Delivery of Combination Drug 

Products via a Novel Dry Powder Delivery Technology. 

Paper presented at the 11th US-Japan Symposium on Drug 

Delivery Systems. Lahaina, Hawaii, December 15-20, 2011. 

Pr 


Dr. Jean C. Sung is the Director of 

Pharmaceutical Development at Pulmatrix, a 

clinical-stage company discovering and 

advancing novel respiratory therapeutics and 

drug delivery technologies. She is responsible 

for Pulmatrix’s formulation, process, and 

analytical development functions. With prior 

experience at Alkermes, Inc. and AIR, Inc. 

(Advanced Inhalation Research), Dr. Sung has 

spent more than a decade developing novel 

particle engineering and formulation 

technologies to advance respiratory dry 

powder drug delivery. Dr. Sung earned her PhD 

and MS in Engineering Sciences with a focus 

on Biomedical Engineering from Harvard 

University and her SB in Chemical Engineering 

from Massachusetts Institute of Technology.

SPECIAL FEATURE 

Transdermal, Topical & 

Subcutaneous: Non-Invasive Delivery 

to Expand Product Line Extensions 

The overall landscape of the transdermal, topical, and subcutaneous markets continue to change - for the better - as non-invasive 

delivery of drugs to the skin or to the systemic circulation via the skin is a highly attractive proposition for many active drugs, be they 

poorly soluble or subject of first-pass metabolism when administered orally. Equally attractive is the possibility of administering 

chronic therapies via the skin, translating to convenience, safety, patience compliance, and drug efficacy. Thus, the pharmaceutical industry has 

an opportunity to expand on product line extensions for existing drugs. 

By: Cindy H. Dubin, Contributor 

In this Drug Development & Delivery feature, delivery system providers and contract developers and manufacturers were asked to 

describe their products and service offerings in their respective area of expertise. 

TRANSDERMAL DRUG DELIVERY 

The transdermal delivery market was valued at $21.5 billion in 2010 and is predicted to reach $31.5 billion by 2015, according to a 

PharmaLive Report. The annual US market for transdermal patches is estimated at more than $3 billion, and transdermal drugs account for 

more than 12% of the global drug delivery market. Transdermal drug delivery prevents many of the problems associated with oral and 

intravenous routes. Major advantages provided by transdermal drug delivery include improved bioavailability, more uniform plasma levels, 

F I G U R E 1 

3M Drug Delivery Systems develops a 

formulation of a drug-in-adhesive (DIA) 

patch product that delivers the drug 

through the skin in the targeted 

therapeutic dose range. 


51


52 

longer duration of action resulting in 

less dosing frequency, reduced side 

effects, and improved therapy due to 

maintenance of plasma levels. 

Transdermal drug delivery is used in 

areas such as pain management and 

women’s health. Pharmaceutical, 

biotechnology, and drug delivery 

companies are poised to tap the hidden 

potential in transdermal drug delivery 

applications, such as wound care, 

monitoring, and diagnostic methods. 

The development of successful 

transdermal drug delivery systems in 

these areas will play an important role 

in improving patient quality of life. 

3M Drug Delivery 

Systems–Putting 

Convenience & 

Compliance Into a Patch 

3M Drug Delivery Systems serves as a 

contract manufacturer to pharmaceutical 

companies that market transdermal products, 

and also helps companies develop and adapt 

their drugs for transdermal delivery. 3M 

Drug Delivery Systems provides 

development services - taking drug products 

and adapting them into the transdermal 

dosage form. 3M Drug Delivery Systems can 

also provide basic contract manufacturing 

services by taking an existing product or one 

that it developed and manufacture it for the 

customer. 

“Clients interested in developing new 

drugs into transdermal products are often 

challenged with being able to achieve 

consistent delivery at the desired rate and 

pharmacokinetic profile to obtain the desired 

therapeutic effect,” says Jordan Fineberg, 

Global Business Manager, Transdermal Drug 

Delivery Systems for 3M Drug Delivery 

Systems. “Fortunately, we are able to provide 

very strong technical capabilities and 

analytics in our labs to help clients overcome 

those technical challenges.” 

To create a passive transdermal product, 

3M Drug Delivery Systems develops a 

F I G U R E 2 

formulation of a drug-in-adhesive (DIA) patch 

product that delivers the drug through the skin 

in the targeted therapeutic dose range. 

“Our DIA systems are versatile enough 

to be compatible with a variety of drugs, and 

our targeted market is companies with APIs 

that fit the transdermal profile. We help our 

customers develop their products in a way 

that achieves a consistent, controlled-release 

dosage level that can be difficult to achieve 

by other forms of administration,” adds Mr. 

Fineberg. 

Transdermal patches are distinguished 

by other systems by the duration for which 

they can be worn. Products can be created 

that deliver multi-day dosing at a very 

specific PK profile. Additionally, continued 

advancements allow this system to deliver 

more than one drug in a single patch, adding 

to convenience for patients. With the ability 

to deliver a controlled release of API over 

multiple days, patient compliance is possibly 

improved. 

“We see continued generic entrants into 

the transdermal market, particularly with a 

couple of big drugs that will go generic in 

the next 3 to 5 years,” predicts Mr. Fineberg. 

“In our own future, we see 3M Drug 

Adhesives Research’s technology is a tailorable, 

pharmaceutical-grade acrylic adhesive that 

secures a patch/device for up to 7 days. 

Delivery Systems working with both branded 

and generic companies in developing and 

manufacturing their transdermal products.” 

Adhesives Research, 

Inc.–Responding to Skin- 

Friendly, Long-Term Wear 

Adhesives 

Adhesives Research specializes in the 

custom development of unique component 

adhesives, films, and laminates for 

transdermal and buccal drug delivery. The 

company offers complete customization of 

our platform technologies (examples such as 

wear-times, moisture vapor transmission, 

shear, etc.) to create the tailored functionality 

required of the adhesives used in a 

customer’s applications. 

Today, many companies are developing 

drug delivery devices that will be bonded to 

the skin for longer periods of time. The 

majority of transdermal patches and drug 

delivery devices available today are dailywear 

devices that are typically removed 

within 24 hours of application; however, 

formulators are developing extended-wear 

patches designed to be worn for multiple 

days, up to a week. In the case of insulin

infusion pumps, the adhesive must reliably 

attach a device to skin while bearing load. 

“While aggressive adhesion ensures a 

secure bond to skin for addressing dosing 

concerns, it can potentially cause discomfort 

upon patch removal,” says Mary Lawson, 

Pharmaceutical Business Manager, Adhesives 

Research, Inc. “Pain is caused when the 

adhesive removes skin cells and/or hair when 

the device is pulled away. Also, an aggressive 

adhesive that releases uncleanly may leave 

behind an unwanted residue on the skin that 

is difficult to remove.” 

In response to the need for skin-friendly, 

long-term wear adhesives, Adhesives 

Research’s newest technology addresses the 

need through a tailorable, pharmaceutical- 

grade acrylic adhesive technology that meets 

the critical design parameters for securing a 

patch/device for periods up to 7 days to 

ensure adequate skin bonding with residue- 

free removal. 

“In spite of the adhesive’s aggressive 

nature, the pain experienced upon removal is 

considered to be low-to-moderate, and 

studies have shown that removal of the 

adhesive tape does not cause disruption of 

the stratum corneum,” says Ms. Lawson. 

As a general rule, adhesives for 

F I G U R E 3 

DBV uses two proprietary manufacturing processes to load active dry compounds onto a polymeric 

film backing. 

transdermal patches are formulated to present 

aggressive bonds with flexibility and 

conformability to ensure the patch or device 

remains firmly in place without lifting or 

fall-off to ensure a therapeutic dose. 

Ms. Lawson explains, “Our long-term 

wear adhesives are designed to withstand 

physical activity, constant friction from 

clothing, periodic moisture exposure, and 

varying degrees of skin porosity and oil 

levels without shifting or moving.” 

Adhesives Research's work is 

complemented by its relationship with its 

subsidiary, ARx LLC, a collaborative 

technology partner. ARx LLC is experienced 

in developing polymer chemistries, that when 

combined with its client’s APIs and 

complementary materials, transform into 

transdermal, transmucosal, and soluble film 

products. This includes single- and multi- 

drug products as well as immediate- and 

controlled-release offerings. ARx LLC 

develops and manufactures innovative 

pharmaceutical products with a focus on 

unique technologies in oral, topical, and 

transdermal drug delivery. The ARx products 

range from first-in-class immediate-release 

OTC and prescription soluble films to multi- 

day, sustained-release transdermal patch 

delivery. The ARx sole objective is to work 

hand-in-hand with its pharmaceutical 

partners to develop and launch 

therapeutically relevant products that have the 

potential to extend a molecule's product 

lifecycle, deliver new compounds, or provide 

better product performance in the areas of 

bioavailability, compliance, and/or cost. 

“The model is evolving in how 

companies talk to us about their product 

design. A decade ago, our partners came to 

us at the onset of a project with a 

predetermined path for integrating a molecule 

into a delivery platform technology,” says 

Megan Greth, Marketing Manager II, ARx, 

LLC. “Today, the conversation is much more 

open from the start of a project and is first 

focused on understanding the improved 

therapeutic outcome followed by evaluating 

the various technologies available for 

delivery. Basically, the conversation has 

evolved to a broader dialogue in which we 

evaluate the best delivery options based on 

the patient population we are targeting. 

“The diversity of the Adhesives 

Research and ARx technology platforms 

inherently enables us to provide design 

F I G U R E 4 

A Dow scientist observing the mixing of a 

topical product and checking for consistency. 


53

flexibility and developmental support to our 

clients from concept to commercialization,” 

Ms. Greth concludes. 

DBV Technologies–Addressing 

Unmet Allergy Treatments for 

Young Children 

According to the World Health 

Organization, allergies constitute the world’s 

fourth largest public health issue and affect 

500 million people worldwide. Allegies affect 

somewhere between 25% and 40% of the 

adult population and more than 50% of 

children in developed countries. 

Environmental, pollution, and changing food 

habits are contributors to the rapid increase in 

the prevalence of allergies. 

DBV Technologies focuses on food and 

pediatric allergy desensitization. The 

company has developed a patented skin 

patch, Viaskin ® that puts the allergen into 

contact with the immune system via immune 

cells present in the superficial layers of the 

skin, while avoiding disruption of the 

blood/skin barrier. This approach, which 

significantly reduces the risk of serious 

anaphylactic shock, enables Viaskin to fulfill 

at least two critically important medical 

needs that were previously unmet, explains 

Pierre-Henri Benhamou, CEO of DBV. First, 

Viaskin targets food allergies, in which the 

risk of anaphylactic shock is high, and 

second, the Viaskin patch is suitable for 

desensitizing children under the age of 5. 

“Therefore, we are in a position to 

address allergies that are not treatable by 

conventional pharmaceutical therapies, he 

says.” 

When Viaskin, containing a specific 

allergen, is applied on the skin, the allergens 

are desposited locally on the skin and are 

taken up by the skin’s immune-competent 

cells, triggering the immune response. The 

allergens are taken up in the superficial 

layers of the skin without crossing the basal 

membrane and preventing the allergen from 

54 

reaching the bloodstream. 


DBV uses two proprietary 

manufacturing processes to load active dry 

compounds onto a polymeric film backing 

via electrostatic force: static powder and 

electrospray deposit, a precise method of 

layering a controlling solution of the allergen 

on the patch so that it is dry and stable. 

DBV has developed Viaskin Peanut for 

peanut allergy, Vaskin Milk for treating IgEmediated 

cow’s milk allergy, and Viaskin 

House Dust Mites for preventing asthma in 

young children. In December 2011, DBV 

received Fast Track Designation for its 

Viaskin Peanut clinical development 

program. 

“This designation was very important 

for us as we believe this translates to a real 

unmet medical need that patients, regulators, 

and DBV are willing to fulfill,” says Mr. 

Benhamou. 

TOPICAL DRUG DELIVERY 

Scientific and technological advances in 

recent decades have widened the scope of 

possibilities for therapies to or via the skin, 

enabling targeted delivery of drugs to 

specific layers of the skin, muscle tissue, or 

even to the systemic circulation with 

unprecedented precision and exactitude. 

Since the advent of the first transdermal 

F I G U R E 5 

Ei Inc. concentrates on developing topical medicines. 

patch in the late 1970s, the pharmaceutical 

industry has witnessed successful delivery of 

chronic therapies like hormones, nicotine, 

and NSAIDS systemically via the skin. These 

innovations have significant advantages over 

the oral route: patient compliance, improved 

plasma levels, and reduced side effects. 

Topical OTC drugs are an important market 

segment with forecast worth expected to 

exceed $870 million in 2014, according to 

Datamonitor. Antiseptic cleansers account for 

the largest part of the topical OTC medicines 

market at almost 60%, with anti-itch products 

in second place at almost 28%, followed by 

anesthetic products, which represent more 

than 10% of the segment. 

Dow Pharmaceutical 

Sciences–A One-Stop-Shop 

Approach to Topical 


Dow Pharmaceutical Sciences provides 

contract development services and clinical 

manufacturing, both sterile and non-sterile, to 

the pharmaceutical and biotechnology 

industries. With a focus being solely on 

topicals, Dow Pharmaceutical Sciences 

spends a lot of time developing ophthalmic 

products. Its newest service, Sterile Product 

Development, supports the development of 

customers’ topical products containing NCEs, 

NMEs, or approved molecules, through to

GMP manufacturing of supplies for Phase I 

and Phase II clinical trials. Clients can access 

all services required to support development 

of their sterile product. These include 

formulation development and in vitro drug 

penetration testing, analytical method 

development, stability testing, GMP & GLP 

manufacturing, labeling, and distribution of 

clinical supplies to test sites worldwide. The 

company provides a full team of specialists 

focused solely on topical product 

development working in one location. 

“Our new One-Stop-Shop provides 

customers with their best chance of success 

and fastest route to market, saving them both 

time and money,” says Vanlee F. Waters, 

Assistant Director of Marketing, Dow 

Pharmaceutical Sciences. 

Dow’s turnkey development process 

includes preformulation (drug solubility, 

excipient, and solvent compatibility) 

evaluations, formula design, and development 

of multiple prototypes. Multiple prototypes 

based on different delivery systems are 

developed to maximize success for chemical 

and physical stability, release from the 

formulation, and penetration into the skin or 

tissue as desired. 

Mr. Waters says that Dow has experience 

in working with the FDA’s Dermatology 

division. “Working closely with the FDA 

F I G U R E 6 

In addition to excipient safety and functionality, characterization of topical formulations for 

sensory attributes is an area in which Gattefossé has expertise. 

provides us with an intimate knowledge of 

their Non-Clinical and Clinical requirements, 

allowing us to get more products approved for 

our customers. Our track record remains 

second to none: 31 New Drug Approvals for 

prescription topical dermatological products 

were approved by the FDA during 2005-11: 

10 of these formulations were developed at 

Dow,” he says. 

Going forward, Mr. Waters says Dow 

will stay the course long-term and continue to 

leverage its focus and experience in topical 

product development. 

“As a boutique CDO provider to large 

and specialty pharma, we will continue to 

leverage our expertise in topical product 

development, non-clinical, clinical, and 

regulatory affairs.” 

Ei Inc.–Laser Focused on 

Topicals 

Ei Inc. is focused solely on topical semi- 

solids and liquids, and it is this expertise that 

Roger Martin, Senior Vice President of Sales 

and Marketing, says makes the company 

stand out in a market that seems to be 

fragmenting into specialty fields. 

“Clients are not really looking for one 

provider to manufacture all of their tablets, 

injectibles, and topicals under one roof. They 

instead want a vendor who is an absolute 

expert at a given dosage form,” he says. 

Clients coming to Ei Inc. are looking for 

topical products, and thus aesthetics and 

stability of the formulation are both very 

important. “Our formulation scientists have 

decades of experience working with various 

APIs used in topical medicines, and they 

work diligently to create both an efficacious 

and pleasant delivery vehicle,” says Mr. 

Martin. 

Critical to Ei’s mission is to protect the 

client’s brand by offering a level of quality 

that never puts their product in jeopardy, and 

service levels that allow them to plan their 

business effectively, Mr. Martin stresses. “By 

offering complete development, analytical, 

stability, and manufacturing services for 

topical products, Ei has positioned itself to 

serve customers in this niche better than any 

other.” 

Ei recently announced its partnership 

with Keranetics in which Ei will start 

manufacturing the API for Keranetic’s wound 

care and burn care products. This is Ei’s first 

venture into API manufacturing. 

“Ei is laser focused on the topical 

marketplace, and we have expanded our 

R&D, analytical, and manufacturing 

capabilities to meet this demand,” explains 

Mr. Martin. “We have heavily invested in both 

people and equipment so that our services can 

meet or exceed the expectations of our 

customers.” 

Gattefossé–Excipients for Safe 

and Effective Topical Delivery 

Gattefossé specializes in topical 

formulations by virtue of the products in its 

offering. Gattefossé designs, manufactures, 

and markets functional excipients globally. 

Each product is developed to meet a unique 

formulation challenge and is supported by 

research and data generated internally. Before 

launching, every excipient is tested to ensure 

a high safety profile and conformity to NF, 

EP, JP, and other well-recognized 

pharmacopoeia. Since 2004, for example, the 

company has been responsible for the 


55


completion of more than 25 NF and EP 

monographs. 

Gattefossé has a range of solubilizers 

and penetration or permeation enhancers. For 

instance, many marketed products already 

include Transcutol ® , an excipient that 

facilitates passage of drugs across the stratum 

corneum, but creates a drug depot effect in 

subcutaneous layers of the epidermis. 

The company has a range of emulsifiers 

for one pot, cold process, and low-energy 

emulsification processes, also coded in 

innumerable products worldwide. The list 

includes Tefose ® 63, a self-emulsifying base, 

known for its innocuity and safety profile for 

mucosal/vaginal delivery of antifungals. 

Other products like Labrafil ® , Labrasol ® , and 

Capryol TM help modulate permeation across 

the epidermis. 

In 2011, Gattefossé announced the 

inauguration of a new research center in 

Saint-Priest, France. Bringing together the 

formulation and R&D laboratories, 

the18,000-sq-ft facility is built to encourage 

and facilitate exchange of ideas and resources 

between various groups engaged in excipient 

characterization and expansion of that 

knowledge in relation to functionality in 

different drug delivery systems. 

“Parallel to safety and regulatory 

qualifications, Gattefossé’s business culture 

places emphasis on understanding the 

specific characteristics and functionality of 

excipients in every formulation design. 

Developing and sharing that knowledge, as to 

how our excipients can help improve, 

differentiate, and innovate customers’ 

products, is the key to the continued success 

of the company,” says Jasmine Musakhanian, 

Marketing & Scientific Director, 

Pharmaceutical Division, Gattefossé USA. 

Characterization of topical formulations 

for sensory attributes (feel, touch, 

spreadability, etc.) is another area in which 

Gattefossé has expertise. “The subject has 

traditionally been of interest to personal care 

customers, but is now expanding to 

56 

pharmaceutical preparations,” Ms. 

Musakhanian adds. 

Selecting the right excipient(s) for the 

intended delivery system, relative to the type 

of active drug entity and its targeted therapy 

is likely to be the key step in saving time and 

cost to market. Gattefossé assists customers 

with the selection process by providing 

pertinent data on physical-chemical 

information and formulation support. 

Skinvisible Pharmaceuticals, 

Inc.–Delivering Tailored 

Molecules 

Skinvisible is an R&D company that 

formulates new products and provides life 

cycle management by revitalizing products 

coming off patent with its patented, targeted 

drug delivery system called Invisicare®. 

Invisicare delivers drugs on, in, or through 

the skin with a controlled release and can be 

tailored to almost any type of molecule. 

Invisicare has multiple applications, 

including topical, transdermal, and mucosal 

(in development). Invisicare is a filmforming 

complex of hydrophilic and 

hydrophobic polymers that are readily 

available and used in the marketplace. 

“Our technology is not encapsulation, it 

is a simple manufacturing process with no 

special equipment and no shearing required. 

It is very compatible (flexible) with both 

water-insoluble and certain cationic active 

ingredients (positive, negative, and neutral) 

and certain water-soluble actives,” explains 

Doreen McMorran, Vice President Business 

Development and Marketing for Skinvisible. 

The formulations do not use alcohol, waxes, 

or other organic solvents and can be 

formulated into creams, lotions, sprays, or 

gels. 

Invisicare represents a “family” of 

Invisicare structures, each specifically 

formulated for specific needs. This includes 

increasing the release of actives (ie, a 3% 

imiquimod formulation can release 30% of 

the active), binding of products (for use for 

F I G U R E 7 

Skinvisible formulations can be formulated 

into creams, lotions, sprays, or gels. 

hand sanitizers, sunscreens, and sunless 

tanning products), and/or photostability of 

avobenzone for 8 hours. 

In 2011, Skinvisible was granted two 

patents: a sunscreen avobenzone 

photostability patent for the US and a 

technology patent for Europe. Skinvisible 

now has 40 patented formulations with 

various indications, all available for licensing 

on an exclusive basis, including a recently 

developed formulation for Netherton 

syndrome for which the company is seeking 

orphan drug status in the US and Europe. 

SUBCUTANEOUS DRUG 

DELIVERY 

Providing innovative, patient friendly 

drug delivery devices is increasingly 

becoming a requirement, not an option, when 

introducing therapeutic products involving 

traditional needle and syringe use as 

evidenced by the prevalence of autoinjections, 

prefilled syringes, and pressure jet 

applicators offered by most large 

pharmaceutical companies today.

F I G U R E 8 

Zosano’s ZP Patch Technology is a needlefree 

delivery system consisting of a patch 

applied by a reusable applicator. 

Zosano Pharma–Using a Patch 

to Overcome the Needle 

Experience 

Although prefilled syringes, auto 

injectors, and pressure jet applicators 

products have improved patient convenience 

and compliance by reducing preparation and 

delivery steps, many patients still associate 

them with a needle experience. Zosano 

Pharma aims for its ZP Patch (formerly 

known as Macroflux) to replace the syringe 

altogether in target compound areas in which 

the patient needs are the highest. 

Zosano’s ZP Patch Technology is a userfriendly, 

simple, and needle-free transdermal 

delivery system consisting of a patch applied 

by either a reusable applicator for therapies 

requiring daily chronic administrations or a 

disposable, single-use patch applicator 

system for acute or short-term applications. 

The ZP patch technology delivers therapeutic 

compounds via drug-coated microneedles on 

the patch that permeate the skin’s outer layer, 

provide rapid and efficient systemic delivery, 

ensure significant therapeutic effect - and is 

painless. Dry-coated drug on the thin 

microneedle patch allows for rapid delivery 

into the skin. The creation of pathways 

through the skin improves control of drug 

distribution throughout the patch treatment 

area, reduces the potential for skin irritation, 

and provides for efficient drug delivery and 

absorption. 

The ZP patch has proven capable of 

delivering a broad range of compounds, 

including peptides, proteins, small 

molecules, and vaccines. It offers the 

reliability and predictability associated with 

a “one-step” application without relying on a 

liquid injection or pre-treatment 

(permeation) in preparation for transdermal 

delivery. 

Zosano Pharma has identified 10 key 

drugs that best fit the criteria for the initial 

product portfolio of the ZP patch. The 

combined market for this portfolio is at least 

$20 to $30 billion dollars in worldwide 

sales. “Current efforts to increase our patch 

dosage delivery dovetails well with the need 

for product differentiation in the expanding 

biosimiliars market and will potentially 

increase the market estimate even further,” 

says Brian Rippie, Director of Business 

Development at Zosano. 

In October 2011, Zosano Pharma 

announced a long-term strategic 

collaboration with Asahi Kasei Pharma 

Corporation (AKP) for the development, 

commercialization, and supply of a weekly 

patch formulation of TeriboneTM (human 

PTH 1-34). As part of this Asian licensing 

agreement, AKP has paid Zosano $7.5 

million in upfront consideration. In addition, 

AKP will pay more than $25 million in 

milestone payments related to development, 

regulatory, and product launch. Zosano will 

receive revenue-based royalties based on 

sales of the ZP patch formulation of 

Teribone in the Asian territories, as well as 

reimbursement for all development and 

manufacturing costs and commercialization. 

AKP is committing significant additional 

financial and technical resources toward the 

development of the patch for the treatment 

of osteoporosis in the Asian territories, and 

has already commenced clinical trials, which 

are now entering the pivotal Phase III stage. 

Zosano retains US/Europe licensing 

rights of ZP patch development of PTH 1- 

34 and expects to further capitalize on the 

momentum gained by its recent 

announcement on this and other products. 

In short, there will be more choices 

available to the patient than ever before 

regarding therapeutics and the delivery 

methods all focused on greater efficacy and 

improved convenience/compliance, says Mr. 

Ripple. 

“We predict a game-changing moment 

once the first effective needle free, pain-free 

drug delivery product enters various markets 

and the expectation of convenient, needlefree 

drug delivery is established,” he 

concludes. 

THE FUTURE OF 

TRANSDERMAL, TOPICAL 

& SUBCUTANEOUS 

DRUG DELIVERY 

Looking forward, the pros predict that 

future growth rate for transdermal, topical, 

and subcutaneous products will be slow to 

moderate. The primary reason for no real 

“revolutionary” products or technologies in 

the near-term future is the fact that most 

pharma and biotech companies continue to 

be very conservative when it comes to earlystage 

development and associated risk. Add 

to that the FDA’s conservative stance toward 

adopting and approving new drugs or new 

delivery systems/technologies, and you have 

another significant growth limiting factor. 

Throw in the financial cliff facing the US by 

year’s end and the future of nationalized 

healthcare, and the picture becomes rather 

murky. u 


57

Gail Schulze 

CEO & Executive Chair 

Thomas of the Board Harlan 

CEO 

Zosano 

Caisson Biotech 

“Caisson’s HepTune involves 

the process of conjugating 

this naturally occurring 

sugar molecule, heparosan, 

to drugs. The size of the 

heparosan and the 

conjugation method for 

coupling can vary depending 

on the drug cargo, the 

client’s/partner’s preference, 

and achievement of optimal 

performance. Caisson works 

to meet the partner’s 

clinical performance needs 

for each drug conjugate.” 

CAISSON BIOTECH: INNOVATION IN 

DRUG DELIVERY USING A NATURALLY 

OCCURRING SUGAR MOLECULE 

Motivated by increasingly reported adverse events related to PEGylated drugs and 

based on the pioneering glycobiology research of Dr. Paul DeAngelis of the 

University of Oklahoma Health Science Center (OUHSC), Caisson Biotech, L.L.C. 

has developed and patented a drug delivery technology utilizing naturally occurring sugar 

polymers to more safely and effectively deliver drugs. Customizable to any currently PEGylated 

drug or to any other molecule requiring this type of stealth modification, HepTuneTM , Caisson’s 

drug delivery system, can be used in the treatment of a number of diseases. Caisson’s patented 

delivery system harnesses the naturally occurring sugar molecule, heparosan, as its delivery 

vehicle. By utilizing proprietary methods to manufacture heparosan and its derivatives, Caisson 

offers its HepTune as a safer delivery vehicle in general and specifically, as an alternative to 

PEG (poly[ethylene glycol]). HepTune has many bio-superior attributes over PEGylation, 

including greater compatibility, lack of accumulation in tissues, extremely desirable PK and 

safety profiles, and no known toxic effects. Additionally, conjugation of Caisson’s heparosanbased 

reagent affords new and novel intellectual property either for new molecules or to extend 

the patent life of already-marketed drugs, and also recaptures the percentage of the market due 

to patients that have developed PEG sensitivity excluding them from current PEGylated 

formulations. Drug Developemnt & Delivery recently spoke with Thomas Harlan, CEO of 

Caisson, to discuss how his company is improving the quality and delivery of numerous 

medications, making life easier for patients, and offering new ways for companies to enhance 

their drug pipeline. 

Q: Can you please provide our 

readers some background on 

Caisson Biotech? 

A: Caisson is a portfolio company of Emergent 

Technologies, Inc. (ETI), a leading technology 

access and innovation management company 

(www.etibio.com). ETI applies rigorous selection 

criteria to assess and evaluate technologies 

emanating from thought-leading scientists in 

universities and federal research labs. Emergent 

then builds commercially viable businesses based 

on those platform technologies. ETI has innovated 

the start-up company management model, allowing 

for effective initial technology transfer, rapid rampup 

or scale-back of business (depending on the 

maturity of the technology), and technical resources 

in response to market needs, aggressive intellectual 

property (IP) protection, and IP scope expansion 


59


60 

and G&A expense cost-sharing. ETI scouted 

the glycobiology research of Dr. DeAngelis, 

and with him (licensing the technology from 

OUHSC) built a family of companies to 

produce and explore applications for three 

commercially important glycosaminoglycan 

(GAG) polymers: hyaluronic acid (HA), 

heparosan, and chondroitin. Collectively, 

these companies (Hyalose, L.L.C., 

Heparinex, L.L.C., and Choncept, L.L.C.) 

have partnered with pharmaceutical and 

biotechnologyy companies to evaluate GAGs 

for application areas ranging across 

rheumatology, ophthalmology, tissue 

engineering, dermal fillers and reconstructive 

surgery, drug delivery, biomaterials, medical 

device coating, and anti-adhesion films. 

Caisson was formed in 2009 as a wholly 

owned subsidiary of Heparinex when Dr. 

DeAngelis’ research on heparosan, in 

particular, began to show bio-superior 

properties over PEG for drug delivery. 

Q: What is it about heparosan 

that makes it Caisson’s drug 

delivery vehicle of choice? 

A: Heparosan is structurally related to 

heparin, one of the most widely used drugs in 

the Pharmacopeia. Heparosan was predicted 

to be biocompatible in the human body as it 

is a natural precursor in the heparin 

biosynthetic pathway and also because of the 

stretches of heparosan that exist in human 

heparan sulfate chains. In addition, certain 

pathogenic bacteria even use a heparosan 

coating to evade the immune system during 

infection. Caisson’s HepTune involves the 

process of conjugating this naturally 

occurring sugar molecule, heparosan, to 

drugs. The size of the heparosan and the 

conjugation method for coupling can vary 

depending on the drug cargo, the 

client’s/partner’s preference, and achievement 

of optimal performance. Caisson works to 

meet the partner’s clinical performance needs 

for each drug conjugate. 

Q: Many companies focus on 

drug delivery technologies. 

What makes Caisson’s HepTune 

unique, and how does is it differ 

from PEGylation? 

A: A significant challenge in the 

pharmaceutical industry exists in which drugs 

are excreted too quickly from the body. This 

can cause patients to endure an increased 

number of treatment injections (requiring 

repeated, either multiple injections in a single 

day or daily injections over an extended 

period of time) and generate strong 

immunogenic responses. Currently, PEG is 

the most widely used drug delivery agent for 

protein-based drugs to overcome these 

problems, but suffers from liabilities, 

including detrimental accumulation in organs 

and antigenicity of its own. Furthermore, 

higher doses and/or lifetime treatments using 

PEG could amplify these problems because 

the liver detoxification system creates a 

variety of reactive PEG metabolites that are 

cytotoxic. There is a rising occurrence of 

PEG immunogenicity. In 1984, anti-PEG 

antibodies were detected in 0.2% of naïve 

patients sampled, but as of 2001, stunningly 

22% to 25% of healthy blood donor samples 

(n = 350) had anti-PEG antibodies. 1 It is 

thought this increase of anti-PEG antibodies 

in the general population is due to the 

increasing use of PEG in consumer products, 

such as toothpaste, laxatives, vitamin pills, 

and many other products commonly used on 

a daily basis. Indeed, some childhood 

leukemia patients no longer respond to their 

PEGylated asparaginase (Oncaspar ® ) 

medication due to anti-PEG antibody levels. 2 

In contrast, the natural heparosan polymers of 

Caisson’s HepTune have the superior 

synergistic combination of biocompatibility, 

lack of immunogenicity, and long half-life in 

the bloodstream. Caisson’s heparosanreagents 

are degraded into normal sugars and 

even recycled into other molecules the body 

uses and thus possess substantially lower 

toxicity. 

Furthermore, the quality control of PEG 

polymer synthesis (ie, the drug delivery 

vehicle) with respect to molecular weight 

distribution is less than optimal. The length of 

the linear polymer is not uniform and 

typically a preparation of linear PEG 

polymers greater than 10 kDa, a portion 

(~3%) of chains might have branching. This 

unplanned branching can yield a series of 

cross-linked complexes containing multiple 

cargo molecules because every branch has a 

reactive group for coupling to the cargo. On 

the other hand, linear heparosan reagents are 

substantially uniform in length, even for 

masses up to 800 kDa. In addition, due to an 

innovative synthesis method involving 

enzymatic polymerization, Caisson’s 

heparosan drug delivery vehicles cannot be 

branched and can never have more than a 

single reactive group. The attachment of the 

heparosan vehicle to drug cargo, has many 

other superior attributes over PEGylation, 

including ease of generating a larger size 

range of polymers, higher water solubility, 

greater biocompatibility of degradation 

products, lack of accumulation in tissues, and 

new intellectual property. In a 2008 Current 

Opinions in Drug Discovery & Development 

article, it was predicted future drugs will use 

higher molecular weight PEGs and/or be 

given at higher doses for long periods.

Caisson predicts heparosan will be the 

preferable therapeutic vehicle based on 

supporting preliminary study results and due 

to PEG’s intrinsic limitations and emerging 

immunogenicity. 

Q: What impact do you see 

Caisson Biotech’s HepTune 

technology having in the 

market? 

A: Caisson Biotech is well positioned to 

have a significant impact in the market in a 

number of ways. Caisson has entered into 

the market with a naturally occurring sugar 

polymer drug delivery vehicle, HepTune, 

with many superior performance benefits 

when compared to current existing 

competitive drug delivery systems. 

Supporting this technology is a very strong 

patent portfolio. Caisson owns or has rights 

to 13 patents, 4 of which are issued. 

Caisson’s aforementioned patents are a 

subset of patents within Dr. DeAngelis’ total 

patent portfolio for carbohydrate production 

consisting of over 200 patents and patent 

applications. 

The Caisson patent claims consist of 

multiple and distinct heparosan production 

methodologies, the use of heparosan as a 

biomaterial and also the use of heparosan 

conjugated to therapeutics. PEG, the base 

material for the PEGylation platform, is a 

publicly available material. Unlike the 

innovators of the PEGylation technology, 

Caisson retains rights to the composition-ofmatter 

and methods-of-manufacture of the 

heparosan conjugation reagent. This 

includes the production of monodisperse 

heparosan materials. The ability to have 

claim coverage related to the production of 

the base material (ie, heparosan) provides 

added protection and exclusivity around the 

ultimate conjugated materials and 

therapeutic products. In addition, Caisson 

benefits from the rights to the control of 

production and supply of the heparosan 

material. 

With the many advantages outlined, 

Caisson believes it is well positioned to 

make a significant impact and contribution 

to the current drug delivery market, greatly 

benefiting pharmaceutical companies and 

ultimately patients. 

Q: What makes Caisson 

Biotech an ideal partner? 

A: Caisson Biotech has a commercially 

proven drug delivery technology, a highly 

motivated and committed staff, and a track 

record of meeting milestones specified in 

contracts, both commercial and grant 

sourced. Caisson’s employees have a 

combined 66 years of experience in the 

Glycobiology field ranging from the 

discovery and manipulation of enzymes 

responsible for synthesis of GAG polymers 

(heparosan, chondroitin, and hyaluronic 

acid) to production and validation of 

heparosan for use in drug delivery. Caisson’s 

founding scientist, Dr. Paul DeAngelis, is 

highly recognized in the Glycobiology field 

for various contributions, both scientifically 

and for his commercial success, and is still 

actively engaged with Caisson on a daily 

basis. Companies interested in evaluating 

HepTune will find the management easy to 

work with, the cost of evaluation very 

affordable, and the process whereby 

conjugates are specified and procured for 

evaluation and testing easy to comprehend 

and comply with. The corporate 

management has developed a simple, timely, 

and effective engagement protocol for 

companies interested in evaluating the 

technology. 

Q: What can we expect to see 

from Caisson in the market? 

A: In May, 2012 Caisson announced Novo 

Nordisk as its first commercialization 

partner. The recently executed 

Developmental License Agreement focuses 

on development of a number of heparosanconjugated 

drugs. One or more of these 

drugs are projected to enter into clinical 

trials between 2013 and 2014. 

Caisson is also developing an internal 

drug pipeline with several products currently 

progressing through preclinical trials. The 

company is gearing up for commercial-scale 

production to handle multiple new clients 

and expects to see active sales and 

marketing efforts by its partners in the US 

and Europe in the near future. Caisson looks 

forward to the rapid advancement of its 

clinical pipeline and the opportunity to work 

with additional industry partners to bring 

novel therapeutics to patients in need. 

References 

1. Garratty G. Progress in modulating the 

RBC membrane to produce transfusable 

universal/stealth donor RBCs. Trans Med 

Rev. 2004;18:245-256. 

2. Armstrong JK, et al. Antibody against 

poly(ethylene glycol) adversely affects 

PEG-asparaginase therapy in acute 

lymphoblastic leukemia patients. Cancer. 

110:103-111. 


61


62 

TRANSDERMAL SYSTEMS & COMPONENTS 

Companies worldwide 

look to 3M Drug 

Delivery Systems for 

ingenious transdermal 

systems and 

components as well as 

manufacturing solutions 

to help accelerate 

development and 

enable success. 3M 

can fulfill all your 

transdermal delivery 

needs, including new microneedle technology. 3M’s microneedle platform, 

Microstructured Transdermal Systems (MTS) leverage core 3M 

competencies to expand the range of transdermally deliverable drugs to 

include proteins, peptides, and vaccines. MTS can also deliver significant 

benefits over injection, including improved delivery efficiency and faster 

absorption of some drugs and vaccines as well as the potential to induce 

similar maximum drug concentrations at a significantly lower dose. Please 

view our latest poster presentation, The Transdermal Delivery of Human 

Growth Hormone, at www.3M.com/tddpublications. For more information, 

call 3M DDS at (800) 643-8086 (US) or visit www.3M.com/MTS. 

CONTRACT TESTING LABORATORY 

Advantar Labs is a top-tier cGMP and GLP Contract Testing Laboratory 

catering to the pharmaceutical, biopharmaceutical, and medical devices 

industries. We offer an exceptional portfolio of scientific services, 

including Method Development and Validation, Method Remediation, 

Preformulation and Formulation Development, Litigation Support, as well 

as Extractables and Leachables. We also provide customized smallscale 

Clinical Trial Packaging and ICH Stability Storage services. Our 

elite team of scientists enables you to increase your clinical success by 

optimizing your CMC strategy and reducing the potential for mistakes 

through our highly efficient lab operations, study protocols, and data 

management systems. For more information, contact Advantar Labs at 

(858) 228-7788 or visit www.advantarlabs.com. 

DRUG DEVELOPMENT SERVICES 

AAIPharma Services Corp. is a leading provider of services that 

encompass the entire pharmaceutical drug development process from 

early development through commercialization. The company, which has 

the benefit of more than 30 years of experience, specializes in analytical 

chemistry, formulation development, clinical packaging, oral drug delivery, 

and contract manufacturing. Headquartered in Wilmington, NC, AAIPharma 

Services serves more than 300 large pharmaceutical and biotechnology 

companies. Our clients say we are experienced, responsive, and 

dependable in: starting rapidly, meeting timelines, seeing obstacles before 

they occur, and responding quickly when things change. Let us move your 

project forward reliably. For more information, contact AAIPharma Services 

Corp. at (800) 575-4224, email at services@aaipharma.com, or visit 

www.aaipharma.com. 

LICENSING & CAPABILITIES 

Aveva has a number of products for license from its development 

pipeline along with a full complement of R&D capabilities to produce 

transdermal drug delivery systems that fortify pipelines and maximize 

product life cycles. Aveva Drug Delivery Systems is one of the world’s 

largest manufacturers of, and a pioneer in, transdermal drug delivery 

systems with a rich history of providing pharmaceutical partners with 

fully integrated, controlled-release transdermal products that fulfill 

unmet market needs. Products for licensing include Sufentanil, 

Fentanyl, Clonidine, and Nicotine. For more information, contact 

Robert Bloder, VP of Business Development, at (954) 624-1374 or 

visit www.avevadds.com.

SOLUBILIZER COMPENDIUM 

BASF’s new solubilizer 

compendium is a must-read for 

anyone working with APIs that 

exhibit poor solubility and 

bioavailability. It leverages BASF’s 

vast expertise in solubilization and 

bioavailabilty enhancement, and is 

the result of many years of 

research. The publication provides 

a valuable overview of all relevant 

BASF excipients (Kolliphor TM 

grades, Soluplus ® , and selected 

Kollidon ® grades), and offers 

helpful advice on creating solid 

solutions and dispersions. What’s 

more, it includes a chapter 

dedicated to high-throughput 

screening as a means of selecting 

the right excipient or combination of excipients for a poorly soluble drug. 

Visit www.innovate-excipients.basf.com to download the compendium as 

a PDF, or to request a free hard copy. BASF’s solubility enhancement 

experts are happy to answer all your questions. Just send an e-mail to 

pharma-ingredients@basf.com. 

PHARMACEUTICAL SOLUTIONS 

Catalent Pharma Solutions is a world leader in patented drug delivery 

technologies. For more than 70 years, we have developed and 

manufactured advanced drug delivery systems and partnered with 

nearly every major global pharmaceutical company. We continually work 

to advance the science of drug delivery and enhance the therapeutic 

and market performance of our customers’ drugs. Our advanced drug 

delivery technologies bring new options to resolve the technical 

challenges development scientists face every day. These patented 

technologies can improve the odds of successful formulation by 

enhancing bioavailability, optimizing the rate of release, and targeting 

the site of absorption. Our technologies include softgel and Vegicaps ® 

Soft capsules; Zydis ® fast-dissolve dosage form; modified-release 

technologies; and a range of inhaled technologies, including MDIs, DPIs, 

nasal sprays, and solutions/suspensions for inhalation, nebulizers, and 

liquid inhalers. For more information, contact Catalent Pharma Solutions 

at (866) 720-3148 or visit www.catalent.com. 

DEVELOPMENT & MANUFACTURING 

Bend Research is a leading independent scientific development and 

manufacturing company with more than 35 years of experience in the 

development of pharmaceutical delivery systems. To achieve its mission of 

improving health through the advancement of its clients’ best new 

medicines, the company uses a multidisciplinary problem-solving 

approach grounded in science and engineering fundamentals to address 

the most difficult challenges. As a leader in novel drug delivery 

technologies and formulations, Bend Research provides expertise in 

solubilization technologies, such as spray-dried dispersions and hot-melt 

extrusion formulations, as well as biotherapeutic, controlled-release, 

inhalation, and nanoparticle technologies. Capabilities include formulation 

science, process development and engineering, dosage-form 

development, cGMP manufacturing, and analytical services for the 

advancement of drug candidates from early discovery to 

commercialization. Bend Research also pioneers, advances, and 

commercializes new technologies. For more information, contact Phoenix 

Ivers of Bend Research at (800) 706-8655 or 

Phoenix.Ivers@BendResearch.com or visit www.BendResearch.com. 

COMBINATION CAPSULE TECHNOLOGY 

InnerCap offers an advanced 

patented multi-phased, multicompartmentalizedcapsularbased 

delivery system. The 

system can be used to enhance 

the value and benefits of 

pharmaceutical and 

biopharmaceutical products. 

Utilizing two-piece hard shell 

capsules, the technology offers 

the industry solutions to 

problems affecting 

pharmaceutical companies, 

patients, and healthcare 

providers. The delivery system 

will be licensed to enhance 

pharmaceutical and 

biopharmaceutical products. It is a very effective way to deliver 

multiple active chemical compounds in different physical phases with 

controlled-release profiles. The delivery system provides the 

pharmaceutical and biopharmaceutical industries with beneficial 

solutions to the industry’s highly publicized need to repackage and 

reformulate existing patented blockbuster drugs with expiring patents 

over the next 5 years. For more information, contact InnerCap 

Technologies, Inc., at (813) 837-0796 or visit www.innercap.com. 


63


64 

MARKETING & COMMUNICATIONS 

Get Noticed. Get 

Funded. Grow 

Faster. When you 

need to connect 

with investors, 

business 

partners, and 

regulatory 

agencies, 

LifeSciencePR 

can make that 

happen. Our 

integrated communication strategies and well-established industry 

contacts will help your life science company achieve its short- and longterm 

corporate objectives. We work seamlessly with your senior 

management team to develop the most effective communication initiatives 

to reach your prospective investors and partners. Our experienced staff 

knows what it takes to break through with your breakthroughs, powering 

your engine in your continued drive toward your success. LifeSciencePR 

will get you there smarter, faster, and easier than any other marketing and 

communications firm in the industry. For more information, contact 

LifeSciencePR at (800) 724-2372 or visit www.LifeSciencePR.net. 

TUNABLE HALF-LIFE TECHNOLOGY 

Novozymes’ tunable 

half-life technology 

has been developed 

to flexibly tune the 

pharmacokinetic 

profile of target 

proteins and 

peptides. The halflife 

of albumin can 

be tuned up or 

down to meet the half-life needs of the customer’s drug and application. 

The technology is based on the interaction between albumin and the 

neonatal Fc receptor (FcRn) to extend circulatory half-life. Building on 

Novozymes’ knowledge of albumin and its native receptor, albumin can 

be modified to increase receptor binding and, consequently, deliver an 

increase in the pharmacokinetics of fused or conjugated therapeutics. 

The Flex technology offers the potential to increase half-life according to 

specific medical needs. This allows delivery of drugs with extended 

circulatory time, therefore reducing dosing regimes and increasing 

patient compliance. For more information on Novozymes’ Flex 

technology, visit www.biopharma.novozymes.com. 

PLATFORM TECHNOLOGY 

Ligand is a biopharmaceutical company that develops and acquires 

technology and royalty revenue generating assets that are coupled to a 

lean cost structure. Ligand’s Captisol ® platform technology is a patent 

protected, chemically modified cyclodextrin with a structure designed to 

optimize the solubility and stability of drugs. Captisol ® has enabled five 

FDA-approved products, including Pfizer’s VFEND ® IV and Baxter’s 

Nexterone ® . For licensing opportunities, call Captisol Services at (877) 

575-5593 or visit www.captisol.com. 

SILICONE MATERIALS 

When it comes to drug delivery, NuSil provides numerous solutions 

that fit a variety of device needs. While most silicone products are 

customized for individual delivery systems, all are developed with 

FDA regulatory concerns in mind. In addition to its role as a supplier, 

NuSil offers research and development capabilities for those looking 

for proprietary, custom formulations. Regardless of batch size, NuSil 

delivers quality, high-performance silicone materials based on your 

unique property requirements, as well as provides precise, custom 

formulations. NuSil offers an even wider range of silicone material 

and compound options for transdermal, transmucosal, implanted 

intrathecal, and external delivery devices, as well as ingestible 

materials. For more information, contact NuSil Technology at (805) 

684-8780 or visit www.nusil.com.


66 

KNOWLEDGE MANAGEMENT 

PharmaCircle is 

an innovative 

knowledge 

management 

company 

specializing in 

the drug 

delivery, 

pharmaceutical, 

and 

biotechnology 

fields, with a current client base ranging from start-up life science 

companies to world leaders in Big Pharma. Clients choose PharmaCircle’s 

services and content for its comprehensive technical (pipeline, products, 

molecule, and technology) and business (deals, acquisitions, royalty, 

licensing, drug revenues, market information, etc) related information and 

analysis, which are ideal for all segments of small and large companies. 

PharmaCircle helps facilitate product life cycle management (LCM), 

partnering, licensing, and competitive intelligence efforts as well as 

supplements internal efforts and costs at a fraction of the cost if 

performed internally. For more information, contact PharmaCircle at (920) 

850-3056 or visit www.pharmacircle.com. 

CONTRACT DIAGNOSTICS 

ResearchDx is the leading Contract Diagnostics Organization (CDO) for the 

biopharmaceutical and diagnostic industries. As a CDO, ResearchDx 

integrates in vitro diagnostics (IVD) non-clinical and clinical research, 

CAP/CLIA laboratory assay discovery, development and testing, GMP 

manufacturing of test kit components, and end-to-end consulting to 

achieve the fastest path to market for your IVD/companion diagnostic. 

With experts managing the entire development process from initial assay 

concept and discovery through clinical research to regulatory approval, 

ResearchDx employs a proactive project management approach with the 

availability of resources to ensure appropriate attention to timelines every 

step of the way. By offering the complete range of CDO services without 

owning a proprietary testing platform, ResearchDx ensures its clients’ 

diagnostics are developed with the methodology and platform that best 

optimize its characteristics and commercialization strategy. For more 

information, contact ResearchDx at (866) 225-9195 or visit 

www.researchdx.com. 

DEVELOPMENT SERVICES DEVELOPMENT SERVICES 

UPM Pharmaceuticals ® is an independent provider of contract 

formulation development, analytical services, and cGMP manufacturing. 

We continue a legacy of intellectual distinction and uncompromising 

performance with every new project. The talent and experience of our 

team, our dedication to science-based formulation design, and our 

commitment to communication and timeliness enables us to offer the 

highest level of customized drug development services. Our 40,000-sqft 

main facility in Baltimore features cGMP pharmaceutical 

manufacturing and packaging suites as well as analytical and R&D 

laboratories staffed by industry veterans. Whatever form your product 

takes, we ensure rigorous and technically sound product 

characterization, methods development, and QC release. Our clients 

enjoy service that is highly responsive and fast with total quality 

management characteristic of a customer-focused business. For more 

information, contact UPM Pharmaceuticals at 410-843-3738 or visit 

www.upm-inc.com. 

Xcelience is a premier provider of formulation development and 

manufacturing solutions with a solid reputation for accelerating early 

phase small molecule development. Our outstanding quality record, 

significant drug development expertise, willingness to customize, and 

disciplined project management enable us to deliver real advantages 

to clients needing to speed potential drugs to clinical trials. Since 

1997, Xcelience has been renowned for reliably expediting drug 

development. Our formulation development scientists have 

considerable experience overcoming challenges associated with 

physical and chemical properties of drug substance, or limited 

quantities of API, in a manner that results in compounds with 

improved solubility and bioavailability. Partnering with a specialist like 

Xcelience for early phase development can significantly reduce 

product risk and accelerate development timelines. For more 

information, contact Xcelience at (608) 643-4444 or visit 

www.xcelience.com.

Drug 


Deuterium Modification as a New Branch of 

Medicinal Chemistry to Develop Novel, Highly 

Differentiated Drugs 

By: Philip Graham, PhD; Julie Liu, PhD; and David Turnquist, MBA; Concert Pharmaceuticals, Inc. 

Introduction 

Concert Pharmaceuticals, a clinical 

stage biopharmaceutical company, uses 

deuterium to create and develop highly 

differentiated new medicines. This is a 

significant departure from the traditional use 

of deuterium modification as an analytical 

probe for metabolic studies. Concert uses its 

DCE PlatformTM (Deuterium Chemical 

Entity) to develop new drugs that are 

designed to have first-in-class or best-inclass 

efficacy and/or safety. Deuterium 

modification provides a novel opportunity to 

develop new drugs by building upon existing 

scientific or clinical experience, potentially 

significantly reducing time, risk, and 

expense. 

Concert’s DCE Platform is based on the 

premise of the deuterium isotope effect 

wherein selective replacement of hydrogen 

atoms with deuterium creates more stable 

chemical bonds with carbon atoms. This 

modification can sometimes improve drug 

metabolism, increase half-life, or enhance 

bioavailability and exposure in a significant 

fashion. Deuterium is a safe, non-radioactive, 

naturally abundant isotope of hydrogen. The 

body of the average human adult already 

contains about 2 g of deuterium. Due to its 

similarity to hydrogen, deuterium 

modification usually has negligible effect on 

the intrinsic activity of a drug at its 

biological target. Concert’s deuterium 

modification drug development approach is 

thus a powerful tool to improve the ADME 

(absorption, distribution, metabolism, and 

elimination) properties of a drug while 

maintaining its intrinsic biological activity. 

As many drugs under development or on the 

market suffer from sub-optimal 

pharmacokinetic and metabolic profiles, 

deuterium modification offers great promise 

to improve the profiles of these drugs and 

open opportunities for new uses. 

Concert has advanced a number of 

deuterium-containing novel compounds 

designed to have unique therapeutic 

properties. The company has made 

preclinical and clinical progress with 

proprietary drug compounds in diverse 

therapeutic areas, including potential 

treatments for diabetic nephropathy, hot 

flashes, spasticity, neuropathic pain, and 

multiple myeloma. 

CTP-499 for Diabetic 

Nephropathy 

Concert’s lead drug candidate is CTP- 

499, a novel potential treatment for diabetic 

nephropathy in type 2 diabetics. Diabetic 

nephropathy is the leading cause of endstage 

renal disease, or kidney failure, and is 

expected to grow significantly as the 

incidence of type 2 diabetes increases 

rapidly. Despite the availability of blood 

pressure lowering agents, such as angiotensin 

II receptor blockers (ARBs) and angiotensinconverting 

enzyme inhibitors (ACEIs), many 

patients continue to experience a decline in 

renal function and progress to kidney failure. 

As a result, there is a critical need for new 

drugs with untapped mechanisms that can 

further delay or prevent the decline of kidney 

function and eventual need for dialysis. 

CTP-499 is an analog of 1-((S)-5hydroxyhexyl)-3,7-dimethylxanthine 

(HDX), 

an active metabolite of Trental ® 

(pentoxifylline), that Concert created by 

SPECIALTY PHARMA JULY/AUGUST 2012 Vol 12 No 6 

67

eplacing several key hydrogen atoms with 

deuterium. Trental, which is significantly 

metabolized to HDX, is approved in the US 

for the treatment of intermittent claudication 

and has been reported in preliminary studies 

to have beneficial effects on urinary albumin 

excretion and renal function decline. Based 

on the pharmacology and degree of exposure, 

it appears these renoprotective effects may be 

due in large part to HDX. CTP-499 and HDX 

have similar physical, chemical, and 

pharmacological properties; however, Phase I 

clinical data with CTP-499 shows that 

incorporation of deuterium leads to increased 

exposure to the species responsible for the 

renoprotective effects. 

To date, four Phase I studies have been 

completed with CTP-499. One study showed 

that controlled-release (CR) formulations of 

CTP-499 form the same metabolites as 

Trental; however, exposure to species 

possessing beneficial anti-inflammatory, anti- 

fibrotic, and immunomodulatory effects was 

increased with CTP-499 relative to Trental 

administration. The overall pharmacokinetic 

profile suggested CR CTP-499 may be 

suitable for once-daily dosing. A second 

study, which tested single ascending doses of 

CR CTP-499, showed that doses up to and 

including 1800 mg were well tolerated. Based 

on these results, CTP-499 shows unique 

potential as a treatment for diabetic 

nephropathy, along with reduced development 

risk given the abundant safety experience 

with Trental. 

In early 2012, Concert initiated a 

6-month Phase II efficacy study of CTP-499 

in diabetic patients with mild-to-moderate 

renal impairment who are at particular risk of 

disease progression due to macroalbuminuria 

(excessive amounts of albumin in their urine). 

The primary goal of the study is to 

investigate the effect of CTP-499 on a 

measure of disease progression, urinary 

albumin excretion, with secondary goals 

related to safety/tolerability and effects on 

renal function and various biomarkers. 

The impact of deuterium on cost of 

goods varies depending on the drug. Concert 

invested in process development research that 

resulted in an elegant, highly efficient 

manufacturing process for CTP-499 active 

pharmaceutical ingredient (API). The 

synthesis has been designed to use the most 

cost-effective deuterated starting material and 

produces API in > 70% yield. Because CTP- 

499 is a single enantiomer, the desired 

enantiomer is directly isolated using an 

asymmetric synthesis with high 

enantioselectivity and little loss of deuterium. 

Finally, Concert creatively implemented 

recycling and recovery techniques through 

which > 90% of the deuterium used is either 

incorporated into the API or recovered for 

future use. CTP-499 is manufactured on a 

scale of hundreds of kilograms and is 

expected to have a cost of goods that is 

competitive with other commercial APIs. 

CTP-347: Deuterium 

Modification of 

Paroxetine 

Concert’s first clinical candidate was 

CTP-347, a selectively deuterated analogue of 

paroxetine. CTP-347 was designed to 

eliminate the irreversible inhibition of a key 

metabolizing enzyme (CYP2D6) caused by a 

highly reactive paroxetine metabolite that 

covalently binds to the enzyme. In certain 

patients potentially benefiting from therapy 

with paroxetine who also receive endocrine 

disrupting agents, such as post-menopausal 

women and cancer patients, paroxetine use 

can be complicated or contraindicated as it 

causes extensive drug-drug interactions 

(DDIs) with other medications. In vitro 

metabolism experiments with CTP-347 

demonstrated little to no CYP2D6 

inactivation, as a result of deuterium-based 

metabolic shunting, which essentially 

prevented the formation of the reactive 

metabolite. Other studies showed the intrinsic 

pharmacology of paroxetine was unchanged 

after deuterium incorporation. A 96-subject 

single and multiple ascending dose clinical 

study with CTP-347 provided further 

evidence, consistent with the in vitro data, 

that irreversible inactivation of the CYP2D6 

enzyme did not occur with CTP-347. This 

clinical study with CTP-347 represents the 

first clinical demonstration that deuteration 

can be utilized to avoid the formation of 

undesired metabolites in humans. 

CTP-354: A Deuterium- 

Modified Subtype- 

Selective GABAA Modulator 

Concert has created deuterated subtypeselective 

GABAA modulators that represent a 

promising therapeutic modality for the 

treatment of spasticity and chronic pain, with 

the potential for improvement over existing 

first-line therapies. A subtype-selective 

GABAA modulator has the potential to 

address a major unmet need by retaining 

desirable therapeutic aspects of the 

benzodiazepines - anxiolytic and spasmolytic 

activity - while minimizing the sedative and 

tolerance effects. 

Concert’s GABAA modulator program is 

based upon agents that have been profiled in 

multiple preclinical efficacy models, 

representing an opportunity to leverage 

extensive therapeutic data to advance a 

clinical candidate. Concert’s GABAA modulator lead compound, CTP-354, is a 

deuterated version of a preclinical agent 

discovered at Merck. The Merck compound, 

L-838417, was targeted by Concert for 

deuterium substitution because its promising 

pharmacology was extensively characterized 

in the literature, although it possessed poor 

pharmacokinetic profiles in preclinical 

species and was never progressed into clinical 

development. L-838417 was shown to have 

desirable GABAA subtype selectivity in vitro: 

no agonist activity at the alpha-1 subtype but 

partial agonism activities at the alpha-2, 69 

SPECIALTY PHARMA JULY/AUGUST 2012 Vol 12 No 6


70 

alpha-3, and alpha-5 subtypes. This in vitro 

subtype profile for L-838417 positively 

translated to its in vivo pharmacology 

profile, with demonstrated preclinical 

efficacy in anxiety, muscle relaxation, 

inflammatory pain, and neuropathic pain, 

and significantly reduced sedation and 

ataxia liabilities in rodents and primates. 

Deuterated CTP-354 demonstrated 

substantial pharmacokinetic improvement 

compared to L-838417 in rats and dogs, and 

has recapitulated beneficial L-838417 

pharmacology in both in vitro and in vivo 

studies. The Chung model, a sciatic nerve 

ligation model of neuropathic pain, was 

performed in the rat to compare oral doses 

of CTP-354 first to L-838417, and then to 

the standard of care, gabapentin. CTP-354 

was efficacious in both studies with a 

prolonged pharmacodynamic effect versus 

L-838417, which correlated with the higher 

CTP-354 plasma level observed at the final 

timepoint. In the comparison of CTP-354 to 

gabapentin, CTP-354 demonstrated an 

excellent dose response and showed 

equivalent efficacy to gabapentin at similar 

doses. At the doses used in these studies, 

CTP-354 was well tolerated in a rat rotarod 

study assessing potential for sedation and 

ataxia. The excellent pharmacokinetic and 

pharmacology profiles of CTP-354 support 

the potential use as a non-sedating treatment 

of spasticity and neuropathic pain. 

C-21359: A Deuterium- 

Stabilized Enantiomer 

of Lenalidomide 

Concert has developed C-21359 as a 

novel deuterated enantiomer of racemic 

lenalidomide (Revlimid ® ), an oncology 

agent indicated for use in multiple myeloma 

and in myelodysplastic syndromes (MDS). 

Revlimid contains a mixture of R and S 

enantiomers that interconvert in vivo. While 

the S enantiomer appears to possess the 

beneficial activities associated with 

Revlimid, dosing of the single S enantiomer 

is not considered useful, as it would rapidly 

convert in vivo to the R/S mixture. Concert 

has discovered a specific deuterium 

modification pattern that optimally slows 

the interconversion of enantiomers, thus 

enabling administration of the more 

beneficial S enantiomer with minimal 

exposure to the R enantiomer. 

C-21359 demonstrates enhanced 

activity versus Revlimid in 

immunomodulatory and anti-cancer in vitro 

efficacy assays. Deuterium-stabilized, single 

S-enantiomer dosing drives this 

improvement in pharmacological efficacy, 

as deuterated racemic lenalidomide 

derivatives show no improvement over 

Revlimid in these assays. C-21359 is 

expected to be useful for the treatment of 

multiple forms of cancer and 

myelodysplastic syndrome, with the 

potential to expand into non-cancer 

indications. 

Summary 

The aforementioned examples show 

that deuterium modification may be used 

broadly to improve upon previously known 

compounds or their analogs, in turn offering 

potential benefits in a wide range of 

therapeutic areas. It should be noted, 

however, that deuterium effects on the 

overall metabolism of a drug are not 

predictable a priori. For example, deuterium 

substitution may have no observable effect, 

or may cause metabolism to shift 

preferentially to another existing pathway. In 

select cases, Concert’s deuterium 

modifications can impart significant 

improvements to the metabolic properties of 

a drug. Thus far, this relatively new 

approach to medicinal chemistry has yielded 

a number of promising drug candidates with 

differentiated therapeutic properties. n 

Dr. Philip 

Graham 

Vice President of 

Program Development, 

Concert 

Pharmaceuticals 

Dr. Philip Graham currently serves as Vice President of 

Program Development at Concert Pharmaceuticals. He 

has more than 20 years experience in the pharmaceutical 

and biotechnology industry. Prior to joining Concert, Dr. 

Graham was Vice President of Product Management and 

Imaging at EPIX Pharmaceuticals, where he also had 

management responsibility for chemical and analytical 

development along with pharmacology and toxicology. 

Before joining EPIX, Dr. Graham worked at Eli Lilly and Co. 

for more than 5 years in analytical development. He earned 

his BS with honors from the University of Otago, New 

Zealand, and his PhD in Analytical Chemistry from the 

University of Massachusetts, Amherst. 

Dr. Julie Fields 

Liu 

Director, Research 

Management, 

Concert 


Dr. Julie Fields Liu is currently Director, Research 

Management at Concert Pharmaceuticals, where she 

serves as a Program Team Leader, Intellectual 

Property/Research Liaison, and Manager of a multi-year 

outsourced chemistry collaboration. She is a medicinal 

chemist and has 12 years of experience in the 

pharmaceutical and biotechnology fields. Prior to joining 

Concert as one of the first 10 employees, Dr. Liu worked 

at Millennium Pharmaceuticals in the areas of oncology, 

inflammation, and metabolic disease. She earned her BS 

in Chemistry with honors and distinction from the 

University of North Carolina at Chapel Hill, and her PhD in 

Organic Chemistry from the University of California, 

Berkeley. 

David Turnquist 

Director of Analytical 

Chemistry, 

Concert 


David Turnquist currently serves as Director of Analytical 

Chemistry at Concert Pharmaceuticals. He has more than 

14 years of experience in the pharmaceutical industry. 

Prior to joining Concert, Mr. Turnquist worked at Vertex 

Pharmaceuticals and Merck Research Laboratories serving 

in a variety of disciplines from Physical and Analytical 

Chemistry to Analytical Development to CMC Project 

Management. He earned his BS in Biology and Chemistry 

from the University of North Carolina at Chapel Hill and his 

MBA from Boston College.

Executive 

Summary 

Q: Can you please discuss AD and its current 

prevalence in the US? 

A: As the number of people 65 years and older in the US continues to 

grow, the number of AD patients will increase. Alzheimer’s is the most 

common cause of dementia, and 13% of all individuals over the age of 

65, or one in eight, have this disease. Alzheimer’s affects the parts of the 

brain that control memory, thought, and language. Doctors do not know 

the exact cause of this disease; however, medical research is working to 

discover what causes it and how to best treat this condition. Alzheimer’s is 

progressive and affects people in different ways. Although each case of 

Alzheimer’s is unique to each specific patient, there are similarities in the 

signs and symptoms that develop as the disease progresses. 

Q: Accera, Inc.’s lead product, Axona ® , targets 

cerebral hypometabolism. Can you explain 

what cerebral hypometabolism is and how 

Axona combats it in AD patients? 

A: One of the hallmark signs of Alzheimer’s is the significant drop 

in the brain’s ability to metabolize glucose, which is the primary 

Holger Kunze 

CEO 

Accera, Inc 

Accera, Inc: Discovering Breakthroughs in 

Treating Central Nervous System Disorders 

Alzheimer’s disease (AD) is the most common cause of dementia. Thirteen percent of all individuals over the age of 

65, or one in eight, have AD. Someone in America develops AD every 69 seconds, and while medications for 

treating AD exist, there is no cure. Accera, Inc., a privately held, fully integrated development and commercialization- 

stage company, is focused on the discovery and development of pioneering therapeutics for serious diseases, such as AD. 

Accera’s lead product, Axona ® , currently marketed in the US as a prescription-only medical food for the clinical dietary 

management of mild-to-moderate AD, addresses metabolic deficiencies and provides an alternative energy source for the 

brains of AD patients. Specialty Pharma recently interviewed Holger Kunze, CEO of Accera, to discuss the company's 

novel approach to treating AD by addressing cerebral hypometabolism. 

source of fuel for the brain. This is known as cerebral 

hypometabolism. Research has shown that decreases in glucose 

metabolism can be seen in the brain 10 to 20 years before any 

clinical AD symptoms appear. Normal, healthy brains depend on 

circulating glucose to carry out most of its functions, including 

memories. Decreases in glucose metabolism correlate with decreases 

in brain function in AD patients. 

Axona is designed to combat cerebral hypometabolism by 

providing the brain with an alternative source of fuel. Axona contains 

caprylic triglyceride, a medium chain triglyceride that is broken 

down by the liver into ketone bodies, which patients can metabolize 

to use as fuel for the brain. 

Q: How does Axona differ from other currently 

available AD treatments? 

A: The first class of FDA-approved medications for AD has been 

formulated to increase the levels of Acetylcholine, a chemical 

responsible for memory in the brain. This class is called 

cholinesterase inhibitors. The primary members of this class are 

Exelon and Aricept. While these treatments have been proven 


71


72 

effective, many AD specialists believe patients benefit from a 

conjunctive or complementary plan that combines different courses 

of treatment. 

In addition, cholinesterase inhibitors do not alleviate the 

cerebral hypometabolism present in the brains of these patients. 

Axona’s ability to provide the brain with an alternative source of 

energy makes it different from all other currently available AD 

treatments. 

Q: Axona comes in a powder form. Can you 

explain how Axona should be administered? 

A: Axona is available in individual powder packets of 40 g per 

packet. It is recommended patients start with a reduced dose of 10 g 

a day and gradually work their way up to a full dose over the course 

of a week. Once acclimated to Axona, patients take only one packet 

of Axona once a day, shortly after breakfast. Axona should be added 

to 4 to 8 ounces of water or other liquids and be fully blended until 

mixed. These are the standard, recommended dosing instructions for 

Axona; however, each patient should work with his or her physician 

to determine the best and most effective dosing strategy. 

Q: Axona is classified as a medical food. What is 

a medical food, and how is it regulated? 

A: The category of medical foods was defined by the FDA in the 

Orphan Drug Act in 1988 as a food that is formulated to be 

consumed orally under the supervision of a physician, and which is 

intended for the specific, dietary management of a disease or 

condition. Medical foods are not subject to the FDA’s full approval 

process for medication; however, medical foods have a generally 

regarded as safe (GRAS) status under the FDA. Medical foods are 

more potent and effective than nutraceuticals and supplements. 

Supplements are intended for normal, healthy adults and do not 

require any pre-market efficacy testing, while medical foods are 

intended to treat patients with a specific illness or disease. Medical 

foods, unlike nutraceuticals and supplements, MUST be taken under 

medical supervision. 

Q: Is there clinical data showing that Axona is 

safe and effective? 

A: Axona has been tested in both a single-dose study and clinical 

trials with patients with mild-to-moderate AD, as well as healthy 

elderly volunteers. The single-dose study was conducted on 20 

patients diagnosed with AD or mild cognitive impairment. The 

results showed a positive response, with improvement in paragraph 

recall and the AD Disease Assessment Scale - Cognitive subscale 

(ADAS-Cog) test. Peer-reviewed results were published in 

Neurobiology of Aging, in 2004. 

Axona was also studied in a double-blind, randomized, 

placebo-controlled study performed at multiple US sites. The trials 

involved 152 patients with mild-to-moderate AD over a period of 90 

days. As Axona is designed to function as a complementary therapy, 

about 80% of those patients were receiving standard-of-care AD 

therapy, including the use of cholinesterase inhibitors and NMDA 

anatagonists. The results showed a significant improvement in 

cognitive function in patients taking Axona after 45 days and 

demonstrated a decline in patients in the placebo group. The results 

also showed that cognitive benefits could be maintained over a 

period of time in the Axona patients. 

Peer-reviewed results were published in Nutrition & 

Metabolism in August 2009 in the article titled Study of the 

Ketogenic Agent AC-1202 in Mild-to-Moderate Alzheimer's 

Disease: a Randomized, Double-Blind, Placebo-Controlled, 

Multicenter Trial. 

Q: Can Axona be taken with the cholerestinase 

inhibitors that are currently available for AD 

patients? 

A: Axona has been designed to complement the existing AD 

therapies currently on the market. Patients in clinical trials were 

permitted to take commonly prescribed AD medications, and 

additional improvements following Axona administration were 

observed even for those patients taking these other medications. 

Q: Who do you see as Axona’s chief competitors? 

A: Among currently available, prescription-only therapies for AD, 

Axona has no direct competitors, as no other AD medication targets 

cerebral hypometabolism. More importantly, as Axona can be taken 

along with cholinesterase inhibitors, it is not competing directly 

with this class. 

Q: Does Accera currently have any partnerships? 

A: Accera is not currently affiliated with any partners, but is 

actively seeking strategic partners interested in advancing 

ccera’s technology to other indications and promoting global 

adoption of Axona. Additionally, Accera is exploring strategic 

partnerships to maximize the commercial success of Axona in 

and outside the US. n

3M 

Company Pg Phone Web Site 

Aveva DDS 

BASF 

Bend Research 

Catalent 

DDL23 

Early Drug Development Summit 2012 

Innercap Technologies 

LifeSciencePR 

Ligand Pharmaceuticals 

Novozymes 

Nusil Technology 

Particle Sciences 

PharmaCircle 

ResearchDx 

Universe of Pre-filled Syringes and Injection Devices 

UPM Pharmaceuticals 

Xcelience 

5 

7 

16 

75 

76 

47 

58 

37 

65 

9 

3 

13 

Insert 

31 

2 

68 

17 

11 

800-643-8086 

954-624-1374 

800-706-8655 

877-576-8457 

+44(0) 1275 849019 

+44 (0) 20 7202 7690 

813-837-0796 

800 - 724-2372 

610-861-4701 

760-436-1199 

866-225-9195 

608-643-4444 

www.3m.com/MTS 

www.avevaDDS.com 

www.soluplus.com 

www.bendresearch.com 

www.catalent.com 

www.ddl-conference.org.uk 

www.eddsummit.com 

www.innercap.com 

www.lifesciencepr.net 

www.captisol.com 

www.stabilizeyourformulation.com 

www.nusil.com/ddd 

www.particlesciences.com 

www.Pharmacircle.com 

www.researchdx.com 

www.pda.org/prefilled2012 

www.upm-inc.com 

www.xcelience.com 


73


74 

On Behalf of Private Equity 

By: John A. Bermingham 

*Disclaimer: This is not a political article to support a candidate for office. 

Throughout the past decade, I have worked for four different 

private equity firms as the CEO of one of their portfolio 

companies. I, like you, have been listening to various parties 

drag private equity firms through the mud disseminating inaccurate 

information about what private equity firms do to companies and their 

people. I have been there, so I believe I am qualified to offer a first- 

hand opinion on private equity firms. 

Private equity firms often buy distressed companies with the 

intention of turning them around, building them up, and then selling 

them in 5 to 7 years for a profit. Most often, this means most of the 

people working in the company keep their jobs following the 

acquisition of the company by a private equity firm and, when the 

company is sold in later years, the people continue on with the 

company and its new owners. However, this is not always the case as 

you will see further on. 

Private equity firms do not buy companies in order to fire all of 

the people and shut down the business. Because many of the 

companies acquired by private equity firms are in serious trouble, one 

of the most common problems in a distressed company is there are 

too many people in the company. This is due to the CEO not wanting 

to lay off people. I found this to be the case in all four private equity- 

owned companies I turned around. 

As an example, let’s say that you become the CEO of a distressed 

company that does $50 million per year in revenue and is losing $5 

million per year. Five years earlier, the company had annual revenue 

of $100 million and required a headcount of 500 people. The 

company still has 500 employees with an overhead expense of $12 

million per year, and your analysis of the head count in the company 

indicates you only need 250 people to generate $50 million in 

revenue. 

Simplistic financial theory shows that reducing headcount by 

50% should cut your overhead expense by 50%, so your expense 

reduction for people would be $6 million. If you are losing $5 million 

per year and cut expenses $6 million per year, you should generate $1 

million in profit, assuming everything else remains the same. 

The idea here is that by reducing headcount to 250 people, you 

save the jobs of the 250 people who are left. If you kept everybody on 

board in the company, under current conditions, the company would 

eventually go bankrupt and then 500 people would lose their jobs! 

So when you hear that such and such company was acquired by a 

private equity firm and they fired lots of people, you most likely have 

only part of the story. The same holds true when you hear of a private 

equity firm buying a company and then shut it down and everyone 

lost their job. The private equity firm most likely acquired a distressed 

company and had to shut it down because they could not save it. 

This is not to say that all private equity firms are good. I have 

seen instances in which a private equity firm acquires a company and 

brings in a new CEO and management team to turn around and 

stabilize the company. Once accomplished, they put the company up 

for sale and in many cases, sell the company to a strategic buyer 

(another company that is in the same business or industry). The 

private equity firm normally makes a lot of money on this type of 

transaction. 

The acquiring company will look to absorb the business into its 

company with a minimal increase in headcount. Hence, the acquiring 

company has no need for most of the people in the company it just 

acquired, so all of those people lose their jobs. 

There is good and bad in almost everything, including private 

equity firms. I just wanted to let you know that not all private equity 

firms are bad, even though some of the media (as well as some 

politicians) portray them as evil personified. u 


John A. Bermingham is currently the Co-President 

and COO of AgraTech, a biotech enterprise focused on 

chitosan, a biomaterial processed from crustacean 

shells (shrimp, crawfish, crab, etc). He was the 

President & CEO of Cord Crafts, LLC, a leading 

manufacturer and marketer of permanent botanicals. 

Prior to Cord Crafts, he was President & CEO of Alco 

Consumer Products, Inc., an importer of house ware, 

home goods, pet, and safety products under the Alco 

brand name and through licenses from the ASPCA and Red Cross. He successfully 

turned around the company in 60 days and sold Alco to a strategic buyer. Mr. 

Bermingham was previously the President & CEO of Lang Holdings, Inc. (an 

innovative leader in the social sentiment and home décor industries) and 

President, Chairman, and CEO of Ampad (a leading manufacturer and distributor 

of office products). With more than 20 years of turnaround experience, he also 

held the positions of Chairman, President, and CEO of Centis, Inc., Smith Corona 

Corporation, and Rolodex Corporation. He turned around several business units of 

AT&T Consumer Products Group and served as the EVP of the Electronics Group 

and President of the Magnetic Products Group, Sony Corporation of America. Mr. 

Bermingham served 3 years in the U.S. Army Signal Corps with responsibility for 

Top Secret Cryptographic Codes and Top Secret Nuclear Release Codes, earned his 

BA in Business Administration from Saint Leo University, and completed the 

Harvard University Graduate School of Business Advanced Management Program.

IN THIS ISSUE - Drug Development & Delivery

Create successful ePaper yourself

Delete template?

Save as template?